1. 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

2. 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

3. 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

4. Maintenance Therapy in Myeloma: Steroids and 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 ;1672
2. Prednisone 50 mg qod prolongs overall and event-free survival after VAD induction therapy
Berenson J. Blood 2002;99:3163

5. Thalidomide: Maintenance Therapy after Autologous Stem Cell Transplant
Initial
dose, mg/d
Maintenance versus no maintenance
CR, %
EFS or PFS, %
OS, %
Attal et al.1
597
400 w/ PAM
67 vs 55*
3-year EFS
52 vs 36
4-year OS
87 vs 77
Barlogie et al.2
668
400
62 vs 43
5-year EFS
56 vs 44
8-year OS
57 vs 44
Spencer et al.3
243
200 w/ steroid
vs steroid alone
63 vs 40*
3-year PFS
42 vs 23
3-year OS
86 vs 75
Lokhorst et al.4
535 50
24 vs 66*
Median
22 m vs 34 m
60 m vs 73 m
vs PAM or none
Attal M, et al. Blood Barlogie B, et al. Blood 2008
Spencer A, et al. J clin Oncol Lokhorst et al . Blood
* CR + VGPR rates. 5 5

6. 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
Slide 10: Bisphosphonates – Mechanisms of action (myeloma-related) 6

7. 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)
Pamidronate
(90 mg/mo)
(n = 196)
Pamidronate
(90 mg/mo) + Thalidomide
(100 mg/day)
(n = 201)
VAD; vincristine, doxorubicin, and dexamethasone
Survival benefit in the combination PAM + Thal arm and not in the single agent PAM arm
Attal M et al Blood 2006; 108: 3289.

8. MRC Myeloma IX: Trial Design for Monthly IV Zoledronic Acid vs Daily Oral Clodronate for Newly Diagnosed MM
RANDOMIZATION
Zoledronic acid (4 mga IV q 3-4 wk) + intensive or non-intensive chemotherapy (n = 981)
N = 1,960
Patients with newly diagnosed MM (stage I, II, III)
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: 8

9. 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)
Risk reduction
P value
0.842 OS
16%
.0118
0.883
PFS
12%
.0179
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 2
Hazard ratio (ZOL versus CLO)
In favor of ZOL
In favor of CLO
a Cox model adjusted for chemotherapy, and minimization factors.
Morgan G, et al. Lancet. 2010;376: 9

10. Bortezomib as Maintenance Therapy VMPT-VT vs VMP: Study Design
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
VT (n=254)
Maintenance: 2 years
BORT 1.3 mg/m2 or maximum dose tolerated q2w
Thalidomide 50 mg/day continuously
R A N D O M I Z E
NDMM
(N=511)
SCT-ineligible
Measurable disease
Karnofsky PS ≥60%
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
No Maintenance Therapy
(N=257)
Endpoints:
Primary: PFS
Secondary: RR, OS, and grade ≥3 AEs
Palumbo A, et al. Presented at: ASH (abstr 200).

11. 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
Reduced risk, %
42 (of progression)
48 (of next therapy)
Median follow-up 54 months
PFS
HR: 0.58 (95% CI, ); P<0.0001
TTNT
HR: 0.52 (95% CI, ); P<0.0001
1.00
0.75
0.50
0.25
0.00
1.00
0.75
0.50
0.25
0.00
Patients, %
Patients, %
VMPT-VT
VMPT-VT
VMP
VMP 10 20 30 40 50 60 70 80 10 20 30 40 50 60 70 80
Time, Months
Time, Months
TTNT=time to next therapy.
Palumbo A, et al. Presented at: ASH (abstr 200).

12. VMPT-VT vs VMP: Overall Survival
Induction
Maintenance
1.00
0.75
0.50
0.25
0.00 10 20 30 40 50 60 70 80
Proportion of Patients
Time, Months
HR: 0.74 (95% CI, ); P=0.04
Efficacy, %
VcMPT-VcT
VcMP
P Value
5-yr PFS 29 13
<0.0001
5-yr TTNT 41 19
5-yr OS 61 51
0.01
3-yr OS from relapse 47 46
0.63
Palumbo A, et al. Presented at: ASH (abstr 200).

13. 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
Cardiologic
Discont. due to AE
11%
Palumbo et al. ASH 2010 (Abstract 620)

14. HOVON-65/GMMG-HD4: Study Design
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)
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)
BORT
1.3 mg/m2
every 2 weeks
Stem cell
collection
and
transplantation*
Thalidomide
50 mg/day
2 years
Patients years of age with newly diagnosed stage II/III MM
(N=744)
Multicenter, International, Phase III Trial
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:

15. HOVON-65/GMMG-HD4: Response, PFS & OS
100 80 60 40 20
100 80 60 40 20
PFS, %
OS, %
PAD
VAD
PAD
VAD
P=0.002
P=0.07 12 24 36 48 60 12 24 36 48 60
Time, Months
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 CR
≥ nCR
≥ VGPR
≥ PR 24 34 56 83 36 49 76 90
<0.001
0.002
Sonneveld P, et al. J Clin Oncol. 2012;30:

16. Maintenance thalidomide (n=87) Maintenance interferon (n=90)
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)
Response before maintenance, % CR
VGPR PR 53 12 33 49 11 37 13
Response improvement with maintenance, %
CR post-maintenance
Increase in CR 74 21 63 15 69
Rosiñol L, et al. ASH 2012, abstract #334; Induction phase publication: Rosiñol L, et al. Blood 2012;120: ; Maintenance therapy previous publication: Rosiñol L, et al. ASH 2011, abstract #3962

17. 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 17

18. Induction Randomization step 1 Maintenance Randomization
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)
or Pred: 50 mg every 48 hrs (VP) VT vs VP VT vs VP
Mateos et al. Lancet Oncol 2010; 11(10):

19. 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%
VTP 25 mos
p=0.1
p=0.3
Mateos et al. Lancet Oncol 2010; 11(10):

20. 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

21. 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 mg daily and tapered w/ neuropathy
Zoledronic acid is continued monthly