The evidence supporting continuous
therapy in multiple myeloma
Sergio Giralt, MD
Chief, Adult Bone Marrow Transplant Service
Memorial Sloan Kettering Cancer Center
New York, New York
Why Maintenance Therapy?
• Induction therapy followed by autologous SCT alone will
cytoreduce but not cure most Multiple Myeloma patients
• Can maintenance therapy:
– prevent or delay disease progression?
– convert partial responses to complete responses?
– improve overall survival?
• Problems with maintenance therapy
– Everybody gets the drug not everybody gets the benefit.
– You “burn” an effective drug.
– Treatment fatigue
• What defines an ideal maintenance strategy?
– Significantly improved outcomes with minimal side effects and
preservation of response to salvage.
Maintenance Therapy
Philosophical Perspective
• Pros
• Cons
• Increases remission duration.
• Exposes all patients to the
side effects of prolonged
treatment.
• Maintains minimal disease
burden preventing end organ
damage.
• Can result in resistant clones.
• Targets “tumor cells” that
leave “dormancy phase”.
• Late effects of long-term
therapy.
• May further decrease tumor
burden post primary therapy.
• Cost
Common wisdom dictates that PFS by itself may not justify continuous
therapy for all patients with a specific disease. Either a survival or QOL
benefit needs to be garnered when comparing continuous therapy to therapy
upon progression. The question is made even more difficult if the issue of preemptive (i.e. early intervention) is included.
Rationale for continuous treatment in the
era of IMID’s and Proteosome Inhibitors
• Primary therapy even with high dose therapy results in CR in less
than 50% of patients.
• Longer treatment can result in better disease control and may be
associated with
– prolonged duration of response
– increased depth of response
• Survival benefit???
• Use of different mechanisms of action (MoAs) of novel agents
• Tolerability of novel agents allows for longer-term treatment
Potential risks of continuous treatment in
the era of IMID’s and Proteosome Inhibitors
• Adverse events related to long-term treatment
– reduced quality of life
– impact on subsequent therapeutic options
– second primary malignancies?
• Reduced survival after relapse
– selection of resistant clones
– availability of non-cross-reacting agents
Historical Perspective
• Long term alkylator therapy associated with higher risk
of 2ry MDS/AML
• Interferon maintenance multiple randomized trials
marginal benefit in PFS no survival benefit. Poor
compliance.
• Long term steroid therapy potentially beneficial
Upgrade in MRD negativity with
consolidation: GIMEMA study
• VTD compared with TD consolidation (x 2 cycles
starting within 3 months post ASCT) on minimal residual
disease (MRD) in MM patients treated in the phase III
GIMEMA trial
• Results (VTD, n = 35; TD, n = 32)
– upgrade in MRD-negativity from 43% to 67% for VTD vs
upgrade from 38% to 52% with TD (p = 0.05 for 67% vs 52%)
– PCR bone marrow analysis showed a median 5 log reduction in
tumour burden with VTD vs a 1 log reduction with TD (p = 0.05)
Terragna, et al. Blood. 2010;116:[abstract 861].
Impact of thalidomide based maintenance
post-ASCT
Patients
(N)
Duration of treatment
CR + VGPR (%)
EFS or PFS (%)
OS (%)
TT21,2
668
Double ASCT
Thal vs no maintenance
until progression
64 vs 43*
(CR only)
p < 0.001
52 vs 41
(5 years)
p = 0.0005
57 vs 44 (8 year)
p = 0.09
Sign in cyto abnormalities
IFM 99-023
597
Double ASCT
Pam + Thal vs Pam vs none
until progression
67 vs 57 vs 55
52 vs 37 vs 36
(3 years)
p < 0.009
87 vs 74 vs 77
(4 years)
p < 0.04
243
Single ASCT
Pred + Thal vs Pred,
12 months
63 vs 40
42 vs 23
(3 years)
p < 0.001
86 vs 75
(3 years)
p = 0.004
Spencer4
Morgan5
• 6/6 trials showed a significant
benefit on PFS
p = 0.03
• 2/6 trials showed a significant benefit on OS +
1/6 showed
a significantNAOS benefit
in patients
Thal vs no maintenance
HR: 1.36; 95%
CI:
820
until progression
1.15–1.61
with cytogenetic abnormalities p < 0.001
NS
Lokhorst6
556
Double or single ASCT
Thal vs alpha-interferon
until progression
66 vs 54
p = 0.005
34 vs 22
p < 0.001
73 vs 60
p = 0.77
Stewart7
332
Single ASCT
Thal + Pred vs observation
until progression
Not reported
28 months vs 17
months
p < 0.0001
Median not reached vs
5 years
P = 0.18
1. Barlogie B, et al. Blood. 2008;112:3115-21. 2. Barlogie B, et al. J Clin Oncol. 2010;28:3023-7. 3. Attal M, et al. Blood.
2006;108:3289-94. 4. Spencer A, et al. J Clin Oncol. 2009;27:1788-93. 5. Morgan GJ, et al. Blood. 2010;116:[623].
6. Lokhorst HM, et al. Blood. 2010;115:1113-20. 7. Stewart AK, et al. Blood. 2010;116:[39].
Impact of bortezomib and thalidomide
maintenance post-ASCT
HOVON-65/GMMG-HD4 trial
100
80
VAD-thalidomide
PAD-bortezomib
Years (%)
78
71
60
50
40
38
42
48
30
20
16
0
CR/nCR premaintenance
CR/nCR postmaintenance
PFS at 3 years
OS at 3 years
* Patients received one (HOVON) or two (GMMG) treatments with high-dose melphalan (HDM) with ASCT.
Sonneveld P, et al. Blood. 2010;116:[abstract 40].
Tales of Two Cases
Case 1
Case 2
•
55 yo female presents with
asymptomatic anemia of 10 gm/dl
and total serum protein 10 gm/lt
•
55 yo female presents with
asymptomatic anemia of 10 gm/dl
and total serum protein 10 gm/lt
•
Work up reveals
– 30 % plasma cells
– Cytogenetic diploid
– IgA kappa peak of 3.2
•
Work up reveals
– 30 % plasma cells
– Cytogenetic t 4,14
– IgA kappa peak of 3.2
– Beta 2 microglobulin of 3.0
– Beta 2 microglobulin of 3.0
•
Receives 4 cycles of Bortezomib
/Thal/Dex
•
Receives 4 cycles of Bortezomib
/Thal/Dex
•
Followed by Auto SCT on Day 60
documented stringent CR
•
Followed by Auto SCT on Day 60
documented paraprotein peak of
0.4 gm/dl
Phase III IFM 2005-02: Lenalidomide as
Consolidation/Maintenance Post-ASCT
Consolidation
N = 614
First-line
ASCT
Lenalidomide: 25 mg/d
Days 1–21/month
2 months
Lenalidomide: 10–15 mg/d
until relapse
≤ 6 months
No PD
< 65 years
Lenalidomide: 25 mg/d
Days 1–21/month
2 months
Primary end point: PFS
Attal et al, 2009.
Placebo until relapse
IFM 2005-02 : PFS from
randomization
.
Arm A
N=307
Arm B
N=307
Progression or Death
143 (47%)
77 (25%)
Median PFS (m)
24 (21-27)
NA
34%
68%
3-year post rando PFS
Hazard Ratio
1
0.46
P
< 107
PFS according to Response PreConsolidation
VGPR or CR
1.00
Len
0.75
0.75
1.00
PR or SD
0.50
0.50
Len
Placebo
0.25
0.25
Placebo
p<10-5
0.00
0.00
p=0.001
0
6
12
18
Placebo
24
30
Revlimid
HR= 0.37 - CI 95% [0.25-0.58]
36
0
6
12
18
Placebo
24
30
Revlimid
HR= 0.54 - CI 95% [0.37-0.78]
36
IFM 2005 02 : Prognostic factors for PFS
Univariate analysis
p
Age
NS
ISS (I / II + III)
NS
Beta-2 m (<=3 / >3)
0.01
Del 13 (Yes / No)
0.06
Induction (VAD / Vel-Dex / Others)
0.04
Response after ASCT (VGPR / no)
0.009
Response after consolidation (VGPR / no)
0.0004
Treatment Arm (A / B)
< 10-7
Multivariate analysis
p
Treatment Arm (A / B)
0.00001
Response after consolidation (VGPR / no)
0.004
Grade 3-4 Adverse Events during
Maintenance
AEs (grade 4)
Arm A
Arm B
Anemia
0%
3% (2%)
Thrombocytopenia
3%
8% (3%)
6% (1%)
31% (7%)
Febrile Neutropenia
0%
0.1%
Infections
4%
8%
0.3%
0.6%
1%
4%
Fatigue
0.6%
2%
Peripheral Neuropathy
0.3%
0.4%
Neoplasia
0.9%
1%
Neutropenia
DVT
Skin disorders
Overall discontinuation due to AEs: XX % placebo versus XX % lenalidomid
CALGB 100104 Schema
Registration
D-S Stage 1-3, < 70 years
> 2 cycles of induction
Attained SD or better
 1 yr from start of therapy
> 2 x 106 CD34 cells/kg
Restaging
Days 90–100
Randomization
Placebo
Mel 200
ASCT
CR
PR
SD
Lenalidomide*
10 mg/d with
↑↓ (5–15 mg)
* provided by Celgene
Corp, Summit, NJ
Stratification based on registration -2M level and prior thalidomide and
lenalidomide use during Induction. Primary Endpoint: powered to determine a
prolongation of TTP from 24 months to 33.6 months (9.6 months)
86 of 128 placebo patients
crossed over to lenalidomide
CALGB 100104, NEJM 2012 ITT Analysis with a median follow-up from transplant of 34
months. P < 0.001 Estimated HR=0.48 (95% CI = 0.36 to
follow up to 10/31/2011
0.63), Median TTP: 46 months versus 27 months.
Median follow-up of 34 months
CALGB 100104, NEJM 2012
follow up to 10/31/2011
35 deaths in the lenalidomide arm and 53 deaths in the
placebo arm. P = 0.028, 3 yr OS 88 vs 80%, HR 0.62 or a
40% reduction in death with the cross over
CALGB 100104, NEJM 2012
follow up to 10/31/2011
The cumulative incidence risk of second primary cancers was greater in the
lenalidomide group (P=0.0008). The cumulative incidence risks ofprogressive
disease (P<0.001)and death (P=0.002) were greater in the placebo group
CALGB 100104, NEJM 2012
After cross over,
most placebo patients
were on lenalidomide
100104: NEJM 2012
CALGB 100104, NEJM 2012
CALGB 100104, NEJM 2012
Tales of Two Cases
Case 1
Case 2
•
55 yo female presents with asymptomatic
anemia of 10 gm/dl and total serum protein
10 gm/lt
•
55 yo female presents with asymptomatic
anemia of 10 gm/dl and total serum
protein 10 gm/lt
•
Work up reveals
– 30 % plasma cells
– Cytogenetic diploid
– IgA kappa peak of 3.2
– Beta 2 microglobulin of 3.0
•
Work up reveals
– 30 % plasma cells
– Cytogenetic t 4,14
– IgA kappa peak of 3.2
– Beta 2 microglobulin of 3.0
•
Receives 4 cycles of Bortezomib /Thal/Dex
•
•
Followed by Auto SCT on Day 60
documented stringent CR
Receives 4 cycles of Bortezomib
/Thal/Dex
•
Followed by Auto SCT on Day 60
documented paraprotein peak of 0.4 gm/dl
THEY BOTH ASK
1) Should they get consolidation?
2) Should they get a 2nd SCT?
3) Should they receive post
transplant lenalidomide?
BMT CTN 0702 StAMINA TRIAL: A Trial of Single Autologous
Transplant with or without RVD Consolidation versus Tandem
Transplant and Maintenance Therapy.
BMT CTN 0702: SCHEMA
Lenalidomide*
Maintenance
Register
and
Randomize
MEL
200mg/m2
VRD x 4*
MEL
200mg/m
2
1.3mg /m2 days 1, 4, 8,11
Lenalidomide 15mg days 1-15
Dexamethasone 40mg days 1, 8, 15
Lenalidomide
Maintenance**
Lenalidomide
Maintenance**
* Bortezomib
**Lenalidomide 15 mg daily x 3years
Monitoring Disease
CR Definition Does Matter With Regards to Depth of
Remission
Number of
Myeloma
Cells
1 × 1012
At diagnosis
Partial response –
50% reduction in M protein
Near complete remission –
immunofixation positive only
Complete remission –
immunofixation negative
Nonquantitative ASO-PCR
1 × 108
1 × 106
1×
MRD
Quantitative ASO-PCR
flow cytometry
104
Rate of molecular CR with HDT is 5%
Common Sense Scenarios
• We may never have randomized data to guide us for
all possible scenarios so clinical judgement is
paramount.
– Low risk patient in CR – maintain or watch?
– High risk patient NOT in CR – continued triple therapy?
• What role for newer agents?
Conclusions
• Continuous treatment strategies are being evaluated in
all phases of myeloma disease from smouldering
myeloma to relapsed/refractory myeloma
• Continuous therapy appeared to
– improve response rates
– prolong PFS/EFS, impact on OS still to be determined
• All novel agents appear to have benefits in longer term
use. Management of adverse events is crucial
• Impact of second primary malignancies not yet fully
understood and should be monitored carefully