1. JIAN HOU, MD
China
• Director, Department of Hematology, the Myeloma &
Lymphoma Center, Shanghai Changzheng Hospital
• Prof. Hou is an expert in the conduct of basic research and
clinical trials and in the identification, characterization and
clinical diagnosis of genetic changes in hematologic
malignancies, especially in myeloma and lymphoma. Dr.
Hou holds multiple leadership positions in the national and
international scientific community of hematology/oncology
including Board Member of the “International myeloma
working group (IMWG)”, member of Chinese Association of
Hematology, and editorial committee of Chinese Journal of
Hematology, Chinese Journal of Leukemia & Lymphoma and
so on.
2. Maintenance Therapy in Myeloma
Jian Hou, M.D. & Ph. D.
Myeloma and Lymphoma Center, Dept. of Hematology
Changzheng Hospital, Shanghai, China
3. Aim of Maintenance
Maintain or Increase response
Prolong duration of response
Prolong survival
better quality of life
4. Concern of maintenance
Which agent is most suitable
How to define treatment duration
Will maintenance drive resistant clones?
12. Lenalidomide: Post ASCT maintenance(PFS)
IFM 2005-021
GALGB1001042
GIMEMA RV2093
Median
PFS
LEN （ n
=307 ）
41m
PBO 23m
Median
TTP
LEN （ n
=231 ）
50m
PBO 27m
Median
PFS
LEN （ n
=231 ）
41.9m
PBO （ n 21.6m
1)Attal M, et al . N Engl J Med 2012. 2) McCarthy P, 14th International Myeloma Workshop 2013; abstract S15-5. 3) Palumbo A, et al. N
Engl J Med. 2014
13. Lenalidomide: Post ASCT maintenance(OS)
IFM 2005-021
GALGB1001042
GIMEMA RV2093
OS(4y)
LEN （ n
=307 ）
73%
PBO （ n 75%
Median
OS
LEN （ n
=231 ）
NR
OS(3y)
LEN （ n
=231 ）
88%
PBO （ n 79.2%1)Attal M, et al . N Engl J Med 2012. 2) McCarthy P, 14th International Myeloma Workshop 2013; abstract S15-5. 3) Palumbo A, et al. N
Engl J Med. 2014
14. Lenalidomide: Post non-ASCT maintenance (PFS)
MM0151
MM0202
Median PFS
MPR-
R （ n=152
）
31m
MPR （ n=15
3 ）
14m
Median
PFS
Rd
continous （ n=53
5 ）
25.5m
Rd18 （ n=541 ） 20.7m
1.Palumbo et al. N Engl J Med 2012 2. Benboubker et al. N Engl J Med 2014
15. Lenalidomide:Post non- ASCT maintenance(OS)
MM0151
MM0202
OS(3y)
MPR-
R （ n=152 ）
70%
MPR （ n=153
）
62%
MP (n=154) 66%
OS(4y)
Rd
continous （ n=53
5 ）
59%
Rd18 （ n=541 ） 56%
MPT(n=547) 51%
1.Palumbo et al. N Engl J Med 2012 2. Benboubker et al. N Engl J Med 2014
18. Lenalidomide maintenance meta-analysis(SPM)
Study name
Odds
ratio
Lower
limit
Upper
limit
p-
Value
IFM 05-02 1.64 0.99 2.72 0.053
CALGB 100104 2.05 1.07 3.93 0.031
MM-015 1.43 0.61 3.34 0.412
RV-MM-P1209 0.85 0.26 2.85 0.798
SUMMARY ESTIMATE 1.62 1.15 2.29 0.006
Above studies, Len was used post transplantation or after a melfalan-containing regimen.
According to result of MM020, Rd continous seemed lower incidence of SPM.
Singh P, et al. ASH 2013. abs 407. 2. Benboubker et al. N Engl J Med 2014
19. HOVON87: MPR-R vs MPT-T
a
Start of maintenance allowed after min 6 cycles induction in case of toxicity not related to LEN/THAL
Zweegman. ASH 2014, abs 179.
Inclusion
Criteria
•Previously
untreated MM
•Age > 65 yrs or
≤ 65 yrs and
ineligible for
ASCT
•WHO-PS: 0-3
in pts < 75 yrs
and 0-2 in pts ≥
75 yrs
MEL: 0.18 mg/kg/day, D1-4
PRED: 2.0 mg/kg/day, D1-4
LEN: 10 mg/day, D1-21
MEL: 0.18 mg/kg/day, D1-4
PRED: 2.0 mg/kg/day, D1-4
THAL: 200 mg/day, D1-28
LEN
10 mg/day
(D1-21) until PD
THAL
100 mg/day
until PD
INDUCTION
Cycles (28 days) 1-9
MAINTENANCEa
Cycles 10+N= 668
Thromboprophylaxis with aspirin or
LMWH
was required in case of previous VTE
20. HOVON87 Trial: Efficacy and Tolerability
Zweegman. ASH 2014, abs 179.
• Median follow-up was 32.6 months
Endpoints MPT-T MPR-R P-value
PFS (mos) 20 22
HR = 0.86,
P = 0.14
Response rate (%)
CR
≥ VGPR
≥ PR
10
49
82
13
44
83
0.43
0.31
0.91
OS (mos) 49 50
HR = 0.79,
P = 0.11
Discontinuations due to AEs, % MPT-T MPR-R P-value
Within 1 yr
Within 2 yrs
28
58
10
16
< 0.001
< 0.001
Median duration of maintenance(m) 5 16 /
21. Author
Randomi
zed
n regimen PFS OS
Sonneveld1
At
diagnosis
827
A:PAD-ASCT-Bort(1.3mg/m2 q2w*2y)
B:VAD-ASCT-Thal(50mg/d)
+
+
(P=0.049)
Mellqvist2
Post-
ASCT
370
A:Bort 1.3mg/m2
*20 doses(7mos)
B:None
+
P=0.05
-
Rosinol3
Post-
ASCT
266
A:Bort1.3mg/m2
d1,4,8,11,q3m*3y+
Thali 100mg qd
B: Thal
C:IFN
+ -
Bortezomib: Post ASCT maintenance
1. Sonneveld P et al. J Clin Oncol. 2012;30:2946.2. Mellqvist U-H et al. Blood. 2013;121:4647.3. Rosinol L et al.
Blood. 2012
22. Author regimen PFS OS
Palumbo1
A:VMP
B:VMP+VT
+ +
Mateos2
A:VMP+VT
VTP+VT
B:VMP+VP
VTP+VP
- -
Bortezomib: Post non-ASCT maintenance
1.Palumbo A et al. J Clin Oncol. 2014;32:634. 2. Mateos et al. Blood.2012120: 2581-2588
23. Phase 3: VMPT-VT vs VMP in newly
diagnosed elderly patients (GIMEMA)
Patients (n=511): >65 years old; median age 71 years
VMPT + VT VMP
Maintenance (until relapse):
Bortezomib (1.3 mg/m2
days 1, 15)
+ Thalidomide (50 mg continuously)
9 x 5-week cycles:*
Bortezomib
Melphalan
Prednisone
No maintenance
*Protocol amendment: from twice-weekly bortezomib dosing (days 1,4,8,11,22,25,29,32) to once-weekly
bortezomib dosing (days 1,8,15,22);
61 patients in VMP arm and 70 patients in VMPT arm received twice-weekly bortezomib dosing.
Palumbo et al. ASH 2012 (Abstract 200), oral presentation
9 x 5-week cycles:*
Bortezomib
Melphalan
Prednisone
thalidomide
24. Time to Next TherapyTime to Next Therapy
Median follow-up 54 months
HR 0.58 (95% CI, 0.47-0.71, P < 0.0001
Patients(%)
Time (months)
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70 80
HR 0.52 (95% CI, 0.42-0.66, P < 0.0001
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70 80
HR 0.52 (95% CI, 0.42-0.66, P < 0.0001
42% Reduced Risk of Progression 48% Reduced Risk of Next Therapy
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70 80
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70 80
Median 35.3 months
Median 24.8 months Median 27.8 months
Median 46.6 months
PFS TTNT*
* Time to next therapy
Progresssion-free survival and time
to next treatmentMedian follow-up: 54 months
Palumbo et al. ASH 2012 (Abstract 200), oral presentation
VMPT + VT
VMP
25. Overall survival
30% reduced risk of death
Overall Survival (OS)
30% Reduced Risk of Death
Overall Survival (OS)
30% Reduced Risk of Death
Patients(%)
Time (months)
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70 80 90
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70 80 90
5-years OS Median OS
VMP
VMPT-VT
51% 60.6 months
61% Not reached
5-years OS Median OS
VMP
VMPT-VT
51% 60.6 months
61% Not reached
HR 0.70, 95% CI, 0.52-0.92, P = 0.01
Off therapyVT MaintenanceVMPT
Palumbo et al. ASH 2012 (Abstract 200), oral presentation
26. Continurous therapy vs Fixed duration of
therapy(CT vs FDT)-Meta Analysis
Palumbo et al. ASH 2013 abs 8515
27. CT vs FDT
Survival Endpoint
CT
(n= 604)
FDT
(n= 614)
HR (P-value)
1-y Landmark Analysis (N= 1218)
Median PFS1 (mos) 32 16 0.47 (< .001)
Median PFS2 (mos) 55 40 0.61 (< .001)
4-y OS (%) 69 60 0.69 (.003)
N= 687
Median second PFS (mos) 15 15 0.76 (.313)
Palumbo et al. ASH 2013 abs 8515
28. Challenges / Open questions
• All patients? High-risk vs standard risk disease?
• Consolidation vs Maintenance or both ?
• MRD-guided post-ASCT treatment strategy ?
• Duration of treatment
– Tolerability & Compliance
– Impact on QoL--Length of treatment-free interval (TFI) associated with
better QoL*
– Appearance of resistant clones
• Impact on options / outcome at relapse?
Personal communication Ulf-Henrik Mellqvist, 2013
29. Summary
• Maintenance therapy with novel agents improved PFS
and likely OS in both eligible and non eligible
transplant patients with MM
• Thalidomide and Lenalidomide had the advantage of
oral administration
• Thalidomide had more frequent peripheral neuropathy
and venous thrombosis
• A sequential approach including bortezomib induction
and Lenalidomide maintenance worth of investigating.
