You are on page 1of 24

Phase 3b UPFRONT Study:

Safety and Efficacy of Weekly


Bortezomib Maintenance Therapy After
Bortezomib-Based Induction Regimens
in Elderly, Newly Diagnosed
Multiple Myeloma Patients
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


Center of Excellence for Lymphoma and Myeloma, Weill Medical College of Cornell University, New
York Presbyterian Hospital, NY; 2Sarah Cannon Research Institute, 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; 7Oncology Hematology Care
Inc., Cincinnati, OH; 8Carroll County Cancer Center, Westminster, MD; 10Millennium Pharmaceuticals,
Inc., Cambridge, MA; 11Florida Cancer Specialists, Fort Myers, FL
1

Background

Patients with multiple myeloma (MM) who are ineligible for HDT-SCT have
limited treatment options
Patients ineligible for HDT-SCT often have a poor prognosis, with shorter TTP, PFS, OS
Elderly MM patients are often ineligible for HDT-SCT due to factors such as age
and co-morbidities

Several bortezomib (Vc)-based regimens have shown activity in newly


diagnosed MM in phase 2 and 3 clinical trials

Treatment

Study design

CR, %

VGPR, %

ORR, %

PFS

VcD1

Induction therapy in 240 younger


patients prior to SCT (2nd transplant
allowed); 4x 3w cycles

38

79

Median:
29.7 Mo

VcTD2

Induction therapy in 199 younger


patients prior to SCT; 3x 3w cycles

21

61

92

93% at 20
Mo

VcMP3,4

Elderly patients (n=60) ineligible for


HDT-SCT; 4x 6w + 5x 5w cycles

32

89

Median:
25 Mo

VcMP5

Elderly patients (n=344) ineligible


for
HDT-SCT; 9x 6w cycles

30

41

71

VcD = Bortezomib and dexamethasone; VcTD = Bortezomib, thalidomide, and dexamethasone; VcMP = Bortezomib, melphalan,
and prednisone
1. Harousseau JL, et al. J Clin Oncol 2010;28:46219.; 2. Cavo M, et al. Blood 2008;112:Abstract 158.; 3. Mateos MV, et al.
Haematologica 2008;93:5605.; 4. Mateao MV, et al. Blood 2006;108:216572.; 5. San Miguel J, et al. NEJM 2008;359:906
17.

Aims

The randomized, open-label, multicenter, phase 3b


UPFRONT study:
compared the efficacy and safety of VcD, VcTD, and VcMP, in
newly diagnosed MM patients ineligible for HDTSCT in the
US community practice setting
investigated the use of single-agent Vc as a maintenance
therapy following induction with VcD, VcTD, or VcMP, in the
non-transplant setting

Objectives and assessments


Primary endpoint:
Progression-free survival
(PFS)

Secondary endpoints included:

Efficacy of VcD, VcTD and VcMP


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

Safety and tolerability of VcD, VcTD and VcMP


Grade 3 adverse events (AEs)
Serious AEs (SAEs)
Peripheral neuropathy (PN)
AEs graded using NCI-CTCAE version 3.0
4

Treatment schema
Induction: 21-day cycles
Cycles 14

Cycles 58

RANDOMIZE 1:1:1

VcD
Vc: 1.3 mg/m2, days 1,4,8,11
D: 20 mg, days 1,2,4,5,8,9,11,12

VcTD
Vc: 1.3 mg/m , days 1,4,8,11
T: 100 mg, days 121
D: 20 mg, days 1,2,4,5,8,9,11,12
2

Maintenance:
35-day cycles
Cycles 913

Vc: 1.3 mg/m2, days 1,4,8,11


D: 20 mg, days 1,2,4,5

Vc: 1.3 mg/m2, days 1,4,8,11


T: 100 mg, days 121
D: 20 mg, days 1,2,4,5

Vc: 1.6 mg/m2,


days 1,8,15,22
Rest period:

days 2335

VcMP
Vc: 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
Interim analysis (IDMC)
[ASH 2009]

Interim analysis (IDMC)


[EHA 2010]
5

Study design
Key inclusion criteria:
Patients 18 years with previously untreated symptomatic MM

Ineligibility for HDTSCT due to age, presence of co-morbid conditions, or


patient preference

Karnofsky Performance Status 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:

VcTD arm: aspirin, full-dose warfarin, or low-molecular weight heparin unless


medically contraindicated1
All groups: prophylaxis for herpes zoster recommended

1. Palumbo A, et al. Leukemia 2008;22:41422.

Data analysis

KaplanMeier PFS analysis was performed on all randomized


patients
Intent to treat (ITT) population, N=502

Efficacy and safety data were analyzed after 100 patients in


each arm had the opportunity to undergo the entire 13-cycle
treatment period
This allowed for a comparison of the efficacy and safety of the VcD,
VcTD and VcMP regimens after 8 induction cycles (I) and 5 Vc
maintenance cycles (M)

Patient demographics and


baseline disease characteristics
VcD
(N=100)
73.5 (3991)

VcTD
(N=100)
73.0 (3888)

VcMP
(N=100)
72.0 (4286)

75 years, %

48

40

34

80 years, %

20

17

13

Male, %

58

45

57

White

78

73

72

Black

19

17

Other

11

10

Not
report
ed

59 / 28 / 13

58 / 28 / 14

63 / 21 / 14

9 / 42 / 48

9 / 38 / 53

13 / 47 / 40

15 / 55 / 29

36 / 33 / 31

26 / 43 / 31

51 / 25 / 24

55 / 30 / 15

62 / 24 / 14

KPS 5060 / 7080 / 90100, %

16

13

13

ISS stage I / II / III, %

4.5

3.4

3.7

Median age, years (range)

Race, %

IgG / IgA /
Light
chain, %

Charlson co-morbidity index 0 /


1 / 2, %

Most common co-morbidities


at baseline (Charlson scale)
VcD

VcTD

VcMP

(N=100)

(N=100)

(N=100)

At least one co-morbidity

47

46

39

Cerebro-vascular disease

Chronic obstructive pulmonary disease

Congestive heart failure

Myocardial infarction

Peripheral vascular disease

Peptic ulcer disease

Renal disease

18

13

Co-morbidity, %

Most common concomitant


medications at baseline
VcD

VcTD

VcMP

(N=100)

(N=100)

(N=100)

At least one concomitant medication

71 (72)

84 (90)

69 (70)

Antiemetics

34 (34)

35 (38)

38 (38)

Antivirals

12 (12)

15 (16)

13 (13)

Any anticoagulant

33 (33)

69 (74)

20 (20)

Beta-blockers

18 (18)

21 (23)

14 (14)

Bisphosphonates

16 (16)

17 (18)

18 (18)

Calcium channel blockers

11 (11)

17 (18)

12 (12)

Cholesterol lowering agents

14 (14)

14 (15)

12 (12)

Constipation management

16 (16)

12 (13)

12 (12)

Diuretics

14 (14)

10 (11)

6 (6)

Narcotics

29 (29)

21 (23)

33 (33)

10 (10)

10 (11)

9 (9)

11 (11)

10 (11)

7 (7)

20 (20)

17 (18)

9 (9)

Class of concomitant medication, n (%)

Non-narcotic analgesics
Oral hypoglycemics
Proton pump inhibitors

10

Treatment exposure
(safety population)

VcD
(N=99)

VcTD
(N=93)

VcMP
(N=99)

No. of treatment cycles


received, median (range)

9 (113)

6 (113)

7 (113)

Patients receiving Vc
maintenance, n

55 (56%)

31 (33%)

43 (43%)

11

Vc dose intensity during


induction and
maintenance
Induction (cycles 18)
Maintenance (cycles 913)

100
90
80

% intended

70
60
50
40

73

76

63

77

69

85

30
20
10
0
VcD

VcTD

VcMP

% intended = Mean Vc doses received / doses planned

12

Investigator-assessed
best confirmed
response rates
(response-evaluable population)
VGPR
Partial response

90

78

Best response category (%)

80
70

40

68
24
36

31

73

44 38

47

34

31

44

40

39

12
8

34

32
32

10

79
71

36

30
20

CR + nCR

71

60
50

VGPR

10

32

31

29

I+M

I+M

0
I

I+M

VcD

VcTD

VcMP
13

PFS
(ITT population N=502)

Proportion of patients

1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

VcD (N=167,

Patients
remaining, n

10

12

14 16 18 20
Time (Months)

VD: 168
VTD: 167

144
134

123
117

95
84

79
71

68
59

50
45

34
32

25
23

20
17

VMP:167

145

125

102

81

69

57

39

32

21

events)

VcTD (N=168,

PFS events)

VcMP (N=167,

PFS events)

22

24

26

28

30

32 34

17
13

15
12

9
6

7
4

16

11

Median follow up was 13.4 months for the entire study population

Median PFS was 13.8, 18.4, and 17.3 months for the VcD, VcTD and VcMP arms,
respectively

None of the pair-wise comparisons are statistically significant

14

Treatment-emergent
grade 3 AEs (safety population)
VcD
I
n (%)

VcTD
M

VcMP
M

At least one grade 3 AE

(N=99)
(N=55)
69 (70)
4 (7)

(N=93)
(N=31)
78 (84) 2 (6)

(N=99)
(N=43)
78 (79)
1 (2)

Peripheral neuropathy

15 (15)

3 (5)

24 (26)

2 (6)

20 (20)

1 (2)

Fatigue

8 (8)

2 (4)

14 (15)

8 (8)

Neutropenia

1 (1)

3 (3)

21 (21)

Diarrhea

8 (8)

3 (5)

4 (4)
(3)

7 (7)

3 (7)

11 (11)

4 (4)

2 (5)

Pneumonia

6 (6)

1
0

15

Treatment-emergent
serious AEs (safety population)
VcD

VcTD

VcMP

n (%)

(N=99)

(N=55)

(N=93)

(N=31)

(N=99)

(N=43)

At least one SAE

49 (49)

7 (13)

52 (56)

5 (16)

47 (47)

3 (7)

Pneumonia

13 (13)

7 (8)

1 (3)

4 (4)

2 (5)

Dehydration

3 (3)

5 (5)

7 (7)

Diarrhea

5 (5)
(5)

3 (3)

4 (4)

1 (2)

7 (8)

4 (4)

2 (2)
(5)

3 (3)

2 (2)

2 (2)

1 (1)

Peripheral
neuropathy
Deep vein
thrombosis

6 (6)

Pulmonary
embolism

3 (3)
(2)

0
1

16

Peripheral neuropathy
(safety population)
VcD
(N=99)

VcTD
(N=93)

VcMP
(N=99)

n (%)
Any grade PN

(N=99)

(N=55)

(N=93)

(N=31)

(N=99)

(N=43)

45 (45)

4 (7)

55 (59)

2(6)

43 (43)

2 (5)

Grade 3 PN

15 (15)

3 (5)

24 (26)
(6)

20 (20)

1 (2)

Any grade PN resulting in


discontinuation of all study drugs

7 (7)

2 (4)

18 (18)

Grade 3 PN resulting in
discontinuation of all study drugs

4 (4)

14 (14)

Median time to PN onset, days


(range)

17 (18)

2 (4)
12 (13)

77 (5316)

63 (3375)
41 (2245)

PN was more common in the VcTD arm compared with the VcD and VcMP arms, both
pre- and post-maintenance with Vc

Incidence of PN did not increase substantially following maintenance


17

QoL: Changes from baseline over the course of


treatment in individual symptom scores

Green = improvement; Red = worsening


The minimal important difference (MID) is 10 for the EORTC QLQ-C30
Questionnaire

QoL poster (abstract 3026): Sunday, Dec 5, Hall A3/A4, Poster board II-906

18

Summary

All three regimens (VcD, VcTD, VcMP) were active in the treatment of
elderly patients with newly diagnosed MM
Grade 3 AEs, serious AEs, PN and study discontinuations due to AEs
were highest in the VcTD arm

Maintenance with single-agent Vc post induction was well tolerated


Compared with post-induction rates, the rates of all-grade and grade 3
PN did not increase substantially in all three treatment arms

Vc maintenance resulted in some increase of VGPR rates in all


three arms

PFS appeared similar between the treatment arms in the ITT


population
Median follow up 13.4 months (ITT population)
Patients continue to be followed for progression and survival status
19

Acknowledgments

The authors would like to thank all UPFRONT patients and study investigators

~200 UPFRONT study sites

20

21

Additional slides
1.

Overall safety profile

2.

Best reduction in baseline M-protein levels after 8 cycles and 13 cycles

22

Overall safety profile


n (%)

VcD
(N=99)

VcTD
(N=93)

VcMP
(N=99)

Any AE

87 (88)

90 (97)

89 (90)

Any drug-related AE

75 (76)

79 (85)

75 (76)

Any grade 3 AE

73 (74)

80 (86)

79 (80)

Any drug-related grade 3 AE

50 (51)

64 (69)

63 (64)

Serious AEs

56 (57)

57 (61)

50 (51)

AEs resulting in discontinuation


of all study drugs

33 (33)

41 (44)

36 (36)

Deaths (within 30 days of last


dose)

8 (8)

6 (6)

6 (6)

Drug-related deaths

2 (2)

1 (1)

1 (1)

23

Best reduction in baseline M-protein


(response-evaluable population)

Best reduction from


baseline M-protein
level, n (%)
100%

VcD
(N=87)

VcTD
(N=81)

VcMP
(N=89)

I+M

I+M

I+M

37 (43)

38 (44)

43 (53)

45 (56)

34 (38)

35 (39)

90%

45 (52)

47 (54)

52 (64)

54 (67)

49 (55)

48 (54)

50%

77 (89)

80 (92)

79 (98)

80 (99)

82 (92)

81 (91)

5 (6)

3 (3)

2 (2)

1 (1)

4 (4)

5 (6)

25<50%

24