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Consolidation and Maintenance in Newly
Diagnosed Symptomatic Multiple Myeloma
Pr Philippe Moreau
Nantes, France

Faculty Disclosure
· Philippe Moreau, MD, has disclosed that he has
received consulting fees from Celgene, Janssen,
and Millennium.

Case Presentation #1
· 58-year-old male
· Symptomatic (bone lesions) ISS2 IgG
multiple myeloma, no 17p, no t(4;14)
normal creatinine, M-spike: 65 g/L
· 4 cycles bortezomib-dexamethasone
partial response 25 g/L followed by
melphalan 200 mg/m2 + ASCT
2 months following ASCT: M-spike: 5 g/L:
very good partial response

Question: Does this patient need further
therapy?
1 No, observation is sufficient
2 Consolidation therapy
3 Maintenance therapy
4 Second ASCT
5 Miniallogeneic stem cell transplantation

Answer: The patient received 4 cycles of
VTD
Do we have data supporting consolidation
therapy?
Yes

Consolidation With VTD After
ASCT
Phase II/III, 39 patients
ASCT conditioning regimens (x 2): Melphalan 200
mg/m2 (n = 25) or 100 mg/m2 (n = 14)
39/39 in VGPR following ASCT
4 cycles of VTD
22% of the patients: true molecular CR
Ladetto M, et al. J Clin Oncol. 2010;28:2077-2084.

Effect of Bortezomib, Thalidomide, and Dexamethasone (VTD) Consolidation Assessed by Nested
Qualitative Polymerase Chain Reaction (PCR)
Ladetto M, et al. J Clin Oncol. 2010;28:2077-2084.

Minimal Residual Disease (MRD) Quantification by Real-Time Polymerase Chain Reaction (RQ-PCR)
Ladetto M, et al. J Clin Oncol. 2010;28:2077-2084.

Clinical Outcome According to Tumor Burden by Quantitative Polymerase Chain Reaction
Ladetto M, et al. J Clin Oncol. 2010;28:2077-2084.

IMWG 2009, Washington
Rajkumar SV, et al. XII IMW. 2009.

Depth of Response
Progression
Treatment initiation
MR
PR
VGPR
nCR
CR
sCR
Time
Depth of response is related to TTP

Phase III Study: Bortezomib Consolidation
vs No Consolidation Following ASCT
Induction + single or double ASCT (n=404)
Randomization (3 months post-ASCT) (n=372)
Bortezomib (n=149)
Observation (n=150)
1.3 mg/m2
Days 1, 4, 8, 11 for two 3-week cycles
then Days 1, 8, 15 for four 4-week
cycles
(total of 20 injections over 21 weeks)
Mellqvist U-H, et al. ASH 2009. Abstract 530.

What is the best consolidation after ASCT?
BMT-CTN study!

BMT/CTN Phase III Study
Lenalidomide
No Consolidation
Maintenance
Register
MEL
VRD x 4
Lenalidomide
and Randomize
200 mg/m2
Maintenance
MEL
Lenalidomide
200 mg/m2
Maintenance
·Active myeloma within 12 months of initial treatment
·Age 70 yrs
·Pts with progressive disease will be excluded
·All pts will have enough PBPC collected for 2 transplants
·Stratify by B2M, response to initial therapy and cytogenetics
·Intent-to-treat analysis. Randomization prior to first ASCT
·New IWG criteria will be used for response assessment
Clinical Trials.gov. NCT01109004.

Case Presentation #1 (continued)
After 4 cycles of VTD: patient is in CR (negative
immunofixation)
Question: Does this patient need further therapy?
1 No, observation is sufficient
2 Maintenance with lenalidomide
3 Maintenance with bortezomib
4 Maintenance with IFN-

Answer: The patient received lenalidomide
10 mg/day continuously
Do we have data supporting maintenance
therapy with lenalidomide ?
Yes

IFM 2005-02: Lenalidomide Maintenance After
ASCT
Phase III prospective randomised, vs placebo
Patients < 65 yr, non-progressive or stable,
6 months post-ASCT
Randomisation
Consolidation
Lenalidomide 25 mg/d, D1-21, 28-day
cycle, during 2 cycles
Lenalidomide
10 -15 mg/d
Placebo
Until progression
until progression
Primary end-point : TTP
Secondary end-points: CR, PFS, OS, feasibility-toxicity
Clinical Trials.gov. NCT00430365.
Attal M, et al. ASCO 2010. Abstract 8018.

HOVON-65/GMMG-HD4 Phase III Trial
Accrual goal:
MM stage II or III, age 18-65 years
800 patients
Randomization
3 x VAD
3 x PAD
CAD + G-CSF
CAD + G-CSF
MEL 200 + PBSCT
MEL 200 + PBSCT
Depending on local
Depending on local
policy for patients
policy for patients
PR MEL 200 + PBSCT
PR MEL 200 + PBSCT
Thalidomide
Bortezomib
50 mg/day for
1.3 mg/m2/2 weeks for
2 years maintenance
2 years maintenance
G-CSF = granulocyte colony stimulating factor;
Sonneveld P, et al. ASH 2008. Abstract 653.
PAD = bortezomib + doxorubicin + dexamethasone.

Case Presentation #2
· 68-year-old male
· Symptomatic (bone lesions) ISS2 IgG
multiple myeloma, no 17p, no t(4;14)
normal creatinine, M-spike: 65 g/L
· 9 cycles VMP very good partial
response

Question: Does this patient need further
therapy?
1 No, observation is sufficient
2 Maintenance with lenalidomide-based
regimen
3 Maintenance with bortezomib-based
regimen
4 Maintenance with IFN-

Answer: The patient received bortezomib +
prednisone maintenance over 2 years
Do we have data supporting maintenance
therapy with bortezomib ?
Yes

Maintenance in Elderly Patients
Mateos MV, et al. Lancet Oncol. 2010;11:934-941.

Toxicity Profile During Maintenance Therapy
Mateos MV, et al. Lancet Oncol. 2010;11:934-941.

Mateos MV, et al.
Lancet Oncol. 2010;11:934-941.

Phase III: VMPT + VT vs VMP in Elderly Patients With
Newly Diagnosed MM GIMEMA Study
·
Patients (n=511): >65 years old; median age 71 years
·
Treatment
VMPT
VMP
9 x 5-week cycles
9 x 5-week cycles
Bortezomib
Bortezomib
Melphalan
Melphalan
Prednisone
Prednisone
Thalidomide
Maintenance:
No maintenance
Bortezomib +
Thalidomide
Bringhen S, et al. Blood. 2010;Aug. 31:[E-pub ahead of print].
Palumbo A, et al. ASH 2009. Abstract 128.

Phase III: VMPT + VT vs VMP
Median follow-up 21.6 months
Time to next therapy
Progression-free survival
1. 00
1. 00
VMPTVT
0. 75
0. 75
VMPT VT
patients
0. 50
0. 50
VMP
of
VMP
%
0. 25
0. 25 VMPT VT: TTNT @ 3 years = 75%
VMPT VT: PFS @ 3 years = 60%
VMP: TTNT @ 3 years = 60%
VMP: PFS @ 3 years = 42%
P = 0.0029
P = 0.007
0. 00
0. 00
0
10
203040
50
0
10
203040
50
Months
Months
PFS comparable in patients with and without t(4;14) or t(14;16) or del17
Palumbo A, et al. ASH 2009. Abstract 128.

MM-015: MPR vs MP for Long-term
Control in Newly Diagnosed MM
51 centres in Europe, Australia, and Israel (N = 459)
Double-blind treatment phase
Up to 9 courses in the absence of PD or unacceptable adverse events
R
Melphalan 0.18 mg/kg, Days
Day 1-4
A
Lenalidom
Lenalido ide
m
Prednisone 2 mg/kg, Days
Day 1-4
Patients
N
D
Lenalidom
Lenalido ide
m
10 mg/day po, Days
Day 1-21
with newly
O
diagnosed,
M
Melphalan 0.18 mg/kg, Days
Day 1-4
untreated
I
Prednisone 2 mg/kg, Days
Day 1-4
Placebo
MM who are
Z
Lenalidom
Lenalido ide
m
10 mg/day po, Days
Day 1-21
not eligible for
A
a transplant
T
Melphalan 0.18 mg/kg, Days
Day 1-4
I
O
Prednisone 2 mg/kg, Days
Day 1-4
Placebo
N
Placebo Days
Day 1-21
Primary endpoint: progression-free survival
Secondary endpoints: OS, TTP, ORR, TTR, duration of response, and quality of life
All patients will receive aspirin prophylaxis (75-100 mg/day)
TTR = time to response.
ClinicalTrials.gov. NCT00405756.

Progression-Free Survival
First Interim Analysis
50% Reduced Risk in PFS
100
Median PFS
(%)
MPR-R
Not reached
75
MP
13.0 months
Event
Median follow up: 9.4 mos
50
ithout
W
25
HR: 0.499
95% CI: 0.330-0.755
Patients
Log-rank P < .001
0
0
5
10
15
20
25
30
PFS
PFS Ti
T me (Mont
n hs))
Palumbo A, et al. ASH 2009. Abstract 613.

MPR-R vs MPR
Landmark PFS Analysis After Cycle 9
75% Reduced Risk in PFS
100
MPR-R
(%)
MPR
75
Event
50
ithout
W
25
HR: 0.245
Patients
95% CI: 0.126-0.476
Log-rank P < .001
0
0
5
10
15
20
No. at Risk
PFS Time (Months)
MPR-R
75
40
17
3
1
MPR
81
21
8
1
1
Palumbo A, et al. EHA 2010. Abstract 0566.

Overall Survival
100
(%)
75
Event
MPR-R
MP
ithout 50
92% 1-year overall survival
W
Patients 25
Total number of deaths: 37
0
05
10
15
20
25
30
OS Time (Months)
Palumbo A, et al. ASH 2009. Abstract 613.

FIRST: Lenalidomide + Low-Dose Dex
vs MPT (IFM 07-01)
Lenalidomide 25 mg/day,
mg/day Days 1-21; every 28 days
Inclusion criteria
Dexamethasone*
Dexamethasone 40 mg/day,
mg/day Days 1, 8, 15, 22;
Until PD
· Previously
P
every 28 days
untreated MM
Eighteen
· Age
A
65 years or
Lenalidomide 25 mg/day,
mg/day Days 1-21; every 28 days
4-week
not a candidate
Dexamethasone*
Dexamethasone 40 mg/day,
mg/day Days 1, 8, 15, 22;
cycles
for transplantation
every 28 days
· No neuropathy
of grade > 2
Melphalan*
Melphalan 0.25 mg/kg/day,
mg/kg/day Days 1-4, every 42 days
Twelve
6-week
·CL
> 30 ml/min
Prednisone 2.0 mg/kg/day,
mg/kg/day Days 1-4, every 42 days
Cr
cycles
Thalidomide*
Thalidomide 200 mg/day,
mg/day daily through 42-day cycle
N = 1590
* In patients older than 75 years: dexamethasone 20 mg/day,
Centres in EU,
melphalan 0.20 mg/kg/day, thalidomide 100 mg/day.
Switzerland, USA,
and Canada
Primary endpoint: progression-free survival

Conclusions
· Consolidation therapy following ASCT is under
evaluation in clinical trials. Possible to achieve
molecular CR.
· Maintenance therapy following ASCT is feasible
and prolongs PFS. Impact on overall survival?
· Maintenance therapy following combination
chemotherapy in elderly patients is feasible and
prolongs PFS. Impact on overall survival?