Maintenance Therapy in Multiple Myeloma
The Role of Other Agents
(Besides Lenalidomide)
James Berenson, MD
Institute for Myeloma and Bone Cancer Research
Los Angeles, CA
Maintenance Therapy in Myeloma
Goals
Reduce the risk of relapse
Extend PFS and OS
 Maintain response achieved following a new
treatment with administration of drugs for a
prolonged time period
 Therapy must be
 Convenient
 Safe and well tolerated LONGTERM
 NOT prevent use or reduce efficacy of other future
treatments
Maintenance Therapy in Myeloma
 In what setting- frontline or > 2nd line
 Most of the data is in the frontline setting
 How long to “maintain” maintenance therapy
 Until relapse or for a fixed length of time
 Trials have employed both approaches BUT no
randomized trials comparing the two w/i a trial
 Which agents




How many to use?
Doses?
Schedule(s)?
Very little data from randomized trials comparing
different maintenance regimens as the only
randomization
Maintenance Therapy in Myeloma:
Steroids and a-Interferon
1. a-Interferon:
a. 929 patients in 8 trials had prolongation of
remission duration and survival by 6 and 5 months
Ludwig H. Ann Oncol 1995;467
b. Twist analysis: IFN gained 9.8 months without
relapse and 5.8 months survival, but with 4.1
months of toxicity
Therefore, benefits must be balanced against toxicity
Ludwig H. 1997;1672
2. Prednisone 50 mg qod prolongs overall and
event-free survival after VAD induction therapy
Berenson J. Blood 2002;99:3163
Thalidomide: Maintenance Therapy
after Autologous Stem Cell Transplant
N
Initial
dose, mg/d
Attal et al.1
597
Barlogie et al.2
668
400
Spencer et al.3
243
200 w/ steroid
vs steroid
alone
Lokhorst et al.4
535
50
1.
3.
400 w/ PAM
vs PAM or none
Attal M, et al. Blood. 2006
Spencer A, et al. J clin Oncol. 2009
Maintenance versus no maintenance
CR, %
EFS or PFS, %
OS, %
67 vs 55*
3-year EFS
52 vs 36
4-year OS
87 vs 77
62 vs 43
5-year EFS
56 vs 44
8-year OS
57 vs 44
3-year PFS
42 vs 23
3-year OS
86 vs 75
Median
22 m vs 34 m
Median
60 m vs 73 m
63 vs 40*
24 vs 66*
2.
4.
Barlogie B, et al. Blood 2008
Lokhorst et al . Blood 2010 * CR + VGPR rates.
Bisphosphonates: Anti-Tumor Effects in MM
 Direct
Induces
apoptosis
Prevents prenylation of GTPases
 Indirect
Reduces
anti-apoptotic and growth factors
Anti-angiogenic
Decreases
angiogenic factors
Prevents endothelial cell development
Inhibits angioattraction
 M2 to M1 reversion of TAMs
Prevents
adhesion of MM cells to stroma
 Synergizes
w/ other anti-MM drugs
 Immune stimulatory effectsIncreases
Vg9d2 T cells
Pamidronate With or Without Thalidomide as
Post-transplantation Maintenance Therapy
• Intergroupe Francophone du Myeloma (IFM) 99 02
– Large, randomized, prospective study
No
maintenance
therapy
(n = 200)
Pts with
untreated
Stage I - III MM
< 65 yrs old
(N = 780)
VAD
regimen
3-4
cycles
Melphalan
140 mg/m2
and
autologous
stem-cell
transplant
Melphalan
200 mg/m2
and second
autologous
stem-cell
transplant
Pts who did
not progress
after 2 mos
(n = 597)
VAD; vincristine, doxorubicin, and dexamethasone
Pamidronate
(90 mg/mo)
(n = 196)
Pamidronate
(90 mg/mo) +
Thalidomide
(100 mg/day)
(n = 201)
Survival benefit in the combination PAM + Thal arm and not in the single agent PAM arm
Attal M et al Blood 2006; 108: 3289.
MRC Myeloma IX: Trial Design for Monthly IV Zoledronic
Acid vs Daily Oral Clodronate for Newly Diagnosed MM
N = 1,960
Patients with newly
diagnosed MM
(stage I, II, III)
•
R
A
N
D
O
M
I
Z
A
T
I
O
N
Zoledronic acid (4 mga IV q 3-4 wk) +
intensive or non-intensive chemotherapy
(n = 981)
Treatment continued at least until disease
progression
Clodronate (1600 mg/d PO) +
intensive or non-intensive chemotherapy
(n = 979)
Endpoints (ZOL vs CLO)
– Primary: PFS, OS, and ORR
– Secondary: Time to first SRE, SRE incidence, and safety
Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS, overall survival,
PFS, progression-free survival; PO, oral; SRE, skeletal-related event; ZOL, zoledronic acid.
a Dose-adjusted for patients with impaired renal function, per the prescribing information.
Morgan G, et al. Lancet. 2010;376:1989-1999.
MRC Myeloma IX:
ZOL Improved OS and PFS vs CLOa
• ZOL significantly reduced the relative risk of death by 16% vs CLO
(HR = 0.842; 95% CI = 0.736, 0.963; P = .0118)
0.883
PFS
0.2
0.4
16%
.0118
12%
.0179
0.6
0.8
1
1.2
1.4
1.6
Hazard ratio (ZOL versus CLO)
In favor of ZOL
a
P value
0.842
OS
0
Risk
reduction
1.8
2
In favor of CLO
Cox model adjusted for chemotherapy, and minimization factors.
Morgan G, et al. Lancet. 2010;376:1989-1999.
Bortezomib as Maintenance Therapy
VMPT-VT vs VMP: Study Design
NDMM
(N=511)
SCT-ineligible
Measurable disease
Karnofsky PS ≥60%
R
A
N
D
O
M
I
Z
E
VMPT (n=254)
Induction: 9 courses
Weekly BORT (4 doses; 1.3
mg/m2)
Melphalan 9 mg/m2
Prednisone 60 mg/m2 once
daily on days 1-4 of each
course
Thalidomide 50 mg/day
continuously
VMP (n=257)
9 courses
Weekly BORT (4 doses; 1.3
mg/m2)
Melphalan 9 mg/m2
Prednisone 60 mg/m2 once
daily on days 1-4 of each
course

Endpoints:
–
Primary: PFS
Secondary: RR, OS, and grade ≥3 AEs
–
Palumbo A, et al. Presented at: ASH. 2012 (abstr 200).
VT (n=254)
Maintenance: 2 years
BORT 1.3 mg/m2 or
maximum dose tolerated
q2w
Thalidomide 50 mg/day
continuously
No Maintenance Therapy
(N=257)
10
VMPT-VT vs VMP: PFS and
Time to Next Therapy (TTNT)
Median PFS, Months
Median TTNT, Months
VMPT-VT
35.3
46.6
VMP
24.8
27.8
42 (of progression)
48 (of next therapy)
Reduced risk, %
Median follow-up 54 months
PFS
1.00
HR: 0.58 (95% CI, 0.47-0.71); P<0.0001
0.75
HR: 0.52 (95% CI, 0.42-0.66); P<0.0001
0.75
Patients, %
Patients, %
TTNT
1.00
VMPT-VT
0.50
VMP
VMP
0.25
0.25
0.00
0.00
0
10
20
30
40
50
Time, Months
60
TTNT=time to next therapy.
Palumbo A, et al. Presented at: ASH. 2012 (abstr 200).
70
80
VMPT-VT
0.50
0
10
20
30
40
50
Time, Months
60
70
80
11
VMPT-VT vs VMP: Overall Survival
Induction
Maintenance
Proportion of Patients
1.00
0.75
VMPT-VT
0.50
VMP
0.25
HR: 0.74 (95% CI, 0.55-0.99); P=0.04
0.00
0
10
20
30
40
50
60
70
80
Time, Months
Efficacy, %
VcMPT-VcT
VcMP
P Value
5-yr PFS
29
13
<0.0001
5-yr TTNT
41
19
<0.0001
5-yr OS
61
51
0.01
3-yr OS from relapse
47
46
0.63
Palumbo A, et al. Presented at: ASH. 2012 (abstr 200).
12
Impact of Maintenance Therapy:
VMPT-VT vs VMP
Landmark analysis after finishing 9 cycles of induction VMPT or VMP
•52% reduced risk of progression with VMPT-VT (HR 0.48, P<0.0001)
– Irrespective of response (CR or PR)
– In pts <75 yrs old, but not ≥75 yrs
•Prognostic factors: response, age, ISS, cytogenetic abnormalities
Grade 3/4 AE’s during maintenance
VMPT-VT
Hematologic
2%
DVT
1%
Sensory neuropathy
6%
Infection
1%
Cardiologic
1%
Discont. due to AE
11%
Palumbo et al. ASH 2010 (Abstract 620)
HOVON-65/GMMG-HD4: Study Design
Multicenter,
International,
Phase III Trial
Patients
18-65 years of
age with
newly
diagnosed
stage II/III MM
(N=744)
PAD × 3 cycles
BORT 1.3 mg/m2
days 1, 4, 8, 11
doxorubicin 9 mg/m2days 1-4
dexamethasone 40 mg days 1-4,
9-12, 17-20
(n=371)
Stem cell
collection
and
transplantation*
BORT
1.3 mg/m2
every
2 weeks
2 years
VAD × 3 cycles
Vincristine 0.4 mg days 1-4
Doxorubicin 9 mg/m2
days 1-4
Dexamethasone 40 mg
days 1-4, 9-12, 17-20
(n=373)
Stem cell
collection
and
transplantation*
• Primary endpoint: PFS
• Secondary endpoints: response, OS, toxicity
*ASCT + melphalan 200 mg/m2; allogeneic SCT with no maintenance offered when possible; German patients enrolled
through GMMG underwent 2 ASCTs.
German centers performed double SCT; Dutch centers performed single SCT.
Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955
Thalidomide
50 mg/day
HOVON-65/GMMG-HD4: Response, PFS & OS
PFS
80
80
60
60
40
PAD
VAD
20
OS
100
OS, %
PFS, %
100
P=0.002
40
PAD
VAD
20
P=0.07
0
0
0
12
24
36
48
Time, Months
60
0
12
24
36
48
60
Time, Months
Improved PFS and OS in pts w/ del 17p13 and those w/ creatinine > 2 mg/dL
Response
VAD Arm: Thalidomide, %
(n=414)
PAD Arm: BORT, %
(n=413)
Pand t Value
24
34
56
83
36
49
76
90
<0.001
<0.001
<0.001
0.002
CR
≥ nCR
≥ VGPR
≥ PR
Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955
Phase III PETHEMA/GEM Trial: Bortezomib as
Maintenance Therapy in Previously Untreated MM1,2
• Endpoints: Primary: PFS; Secondary: response rate, OS, safety
• Patients: 266 pts <65 yrs of age with previously untreated MM randomized to
•
maintenance therapy; median age 56–58 yrs across arms; 53–59% ISS stage
II/III across arms
Dose and schedule:
 Induction: thalidomide/Dex (6 cycles) vs VTD (6 cycles) vs VBMCP/VBAD (4 cycles) +
bortezomib (2 cycles); followed by ASCT with MEL-200; then second randomization to:
 Maintenance: 3 arms
•
•
•
bortezomib 1.3 mg/m2 days 1, 4, 8, 11 every 3 mos + thalidomide 100 mg/day (VT)
thalidomide 100 mg/day
interferon-α2b 3 MU 3 times/week; for 3 yrs
• Response:
Maintenance
VT (n=89)
Maintenance
thalidomide (n=87)
Maintenance
interferon (n=90)
49
11
37
53
13
33
63
15
69
15
Response before maintenance, %
CR
VGPR
PR
53
12
33
Response improvement with maintenance, %
CR post-maintenance
Increase in CR
74
21
Rosiñol L, et al. ASH 2012, abstract #334; Induction phase publication: Rosiñol L, et al. Blood 2012;120:1589-1596; Maintenance therapy previous publication: Rosiñol L, et al.
ASH 2011, abstract #3962
Phase III PETHEMA/GEM Trial: Bortezomib as
Maintenance Therapy for Previously Untreated MM1,2
• Outcomes: Median follow-up of 34.9 mos; from
onset of maintenance therapy:
 PFS: addition of bortezomib to thalidomide (VT) maintenance
resulted in significantly longer PFS vs thalidomide or interferon
(p=0.0009)
 OS: No difference between arms (p=0.47)
 Bortezomib-containing (VT) maintenance conferred a
significant PFS advantage in pts with low-risk (p=0.002) but
not high-risk (p=0.5) cytogenetics
• Safety:
 Gr 3/4 thrombocytopenia for VT vs. thalidomide: 10% vs. 2%;
p=0.01
 Gr 3/4 neutropenia: Approximately 13% for VT, 16% for
thalidomide, and 17% for interferon
*p=0.02 vs thalidomide; #p=0.06 vs thalidomide; †discontinued thalidomide but remained on bortezomib
Rosiñol L, et al. ASH 2012, abstract #334
Phase III: VMP vs VTP in Newly Diagnosed Elderly
Pts with MM (PETHEMA/GEM Study)
• Pts (n=260), >65 yrs old (median age 73 yrs)
• Multicenter, two-stage randomized trial
Induction Randomization step 1
Induction (max. 6 cycles)
• One 6-wk cycle, bortezomib 2x wkly
• Five 5-wk cycles, bortezomib 1x wkly
VMP
vs
VTP
Maintenance Randomization
step 2
Maintenance (up to 3 yrs)
Bortezomib: 1.3 mg/m2
(d 1, 4, 8, 11), every 3 mos
+ Thal: 50 mg daily (VT)
VT
vs
VP
VT
vs
VP
or Pred: 50 mg every 48 hrs (VP)
Mateos et al. Lancet Oncol 2010; 11(10): 934-941
PFS and OS
• No significant difference in PFS and OS between VMP and VTP
groups and not significantly different for VT or VP maintenance
PFS
OS
VMP 3-yr OS 74%
VMP 34 mos
VTP 3-yr OS 65%
p=0.1
VTP 25 mos
p=0.3
Mateos et al. Lancet Oncol 2010; 11(10): 934-941
Summary
 The role of maintenance therapy with novel
agents has not been clearly defined (limitations
in trial designs)
 Long term use appears to be safe w/
bortezomib and steroids
 Better trial designs are required to clarify the
role of maintenance therapy in myeloma
 Specific drugs
 Single agent vs combination
 Doses and schedules
 Length of therapy- fixed vs to progression
 Endpoints- PFS vs OS
In Our Clinical Practice
 Maintenance therapy is used for all patients responding
in both the frontline and salvage settings
 Drugs are continued until progressive disease;
however, doses may have to be reduced or
discontinued due to toxicity
 Drugs are continued that were part of the treatment
regimen EXCEPT chemotherapy
 New agents are NOT introduced during maintenance
(i.e. the devil you know is better (and shown to be effective)
than the one you don’t)- if so, this is NEW treatment
 Steroids at equivalent dose intensity (160 mg Dex)/month
as oral methylprednisolone qod alone or w/ IV Dex qow
 Bortezomib 1.3 mg/m2 sc qow
 IMiD drugs- Lenalidomide 10 mg for 14 or 21 days
depending on regimen; THAL 50-100 mg daily and tapered
w/ neuropathy
 Zoledronic acid is continued monthly