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MAINTENANCE THERAPY IN MULTIPLE MYELOMA
1. 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
2. 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.
3. Maintenance Therapy
Philosophical Perspective
• Pros
• Increases remission duration.
• Maintains minimal disease
burden preventing end organ
damage.
• Targets “tumor cells” that
leave “dormancy phase”.
• May further decrease tumor
burden post primary therapy.
• Cons
• Exposes all patients to the
side effects of prolonged
treatment.
• Can result in resistant clones.
• Late effects of long-term
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 pre-
emptive (i.e. early intervention) is included.
4. 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
5. 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
6. 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
7. 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].
8. 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
p = 0.03
52 vs 37 vs 36
(3 years)
p < 0.009
87 vs 74 vs 77
(4 years)
p < 0.04
Spencer4
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
Morgan5
820 Thal vs no maintenance
until progression
NA HR: 1.36; 95% CI:
1.15–1.61
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
Impact of thalidomide based maintenance
post-ASCT
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].
• 6/6 trials showed a significant benefit on PFS
• 2/6 trials showed a significant benefit on OS +
1/6 showed a significant OS benefit in patients
with cytogenetic abnormalities
9. Impact of bortezomib and thalidomide
maintenance post-ASCT
16
38
42
71
30
50 48
78
0
20
40
60
80
100
CR/nCR pre-
maintenance
CR/nCR post-
maintenance
PFS at 3 years OS at 3 years
VAD-thalidomide
PAD-bortezomib
Sonneveld P, et al. Blood. 2010;116:[abstract 40].
* Patients received one (HOVON) or two (GMMG) treatments with high-dose melphalan (HDM) with ASCT.
Years(%)
HOVON-65/GMMG-HD4 trial
10. Tales of Two Cases
Case 1
• 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
• Receives 4 cycles of
Bortezomib /Thal/Dex
• Followed by Auto SCT on Day 60
documented stringent CR
Case 2
• 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 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 paraprotein peak of
0.4 gm/dl
11. Phase III IFM 2005-02: Lenalidomide asPhase III IFM 2005-02: Lenalidomide as
Consolidation/Maintenance Post-ASCTConsolidation/Maintenance Post-ASCT
First-line
ASCT
< 65 years
Lenalidomide: 25 mg/d
Days 1–21/month
2 months
Primary end point: PFS
≤ 6 months
No PD
N = 614
Lenalidomide: 10–15 mg/d
until relapse
Lenalidomide: 25 mg/d
Days 1–21/month
2 months
Placebo until relapse
Consolidation
Attal et al, 2009.
12. IFM 2005-02 : PFS from
randomization
. Arm A
N=307
Arm B
N=307
P
Progression or
Death
143 (47%) 77 (25%)
Median PFS (m) 24 (21-27) NA
3-year post rando
PFS
34% 68%
Hazard Ratio 1 0.46
<
10-7
13. PFS according to Response Pre-
Consolidation
HR= 0.37 - CI 95% [0.25-0.58] HR= 0.54 - CI 95% [0.37-0.78]
PR or SD VGPR or CR
0.000.250.500.751.00
0 6 12 18 24 30 36
Placebo Revlimid
0.000.250.500.751.00
0 6 12 18 24 30 36
Placebo Revlimid
p<10-5
p=0.001
Placebo
Placebo
Len
Len
14. IFM 2005 02 : Prognostic factors for PFS
Univariate analysisUnivariate analysis pp
AgeAge NSNS
ISS (I / II + III)ISS (I / II + III) NSNS
Beta-2 m (<=3 / >3)Beta-2 m (<=3 / >3) 0.010.01
Del 13 (Yes / No)Del 13 (Yes / No) 0.060.06
Induction (VAD / Vel-Dex / Others)Induction (VAD / Vel-Dex / Others) 0.040.04
Response after ASCT (VGPR / no)Response after ASCT (VGPR / no) 0.0090.009
Response after consolidation (VGPR / no)Response after consolidation (VGPR / no) 0.00040.0004
Treatment Arm (A / B)Treatment Arm (A / B) < 10< 10-7-7
Multivariate analysisMultivariate analysis pp
Treatment Arm (A / B)Treatment Arm (A / B) 0.000010.00001
Response after consolidation (VGPR / no)Response after consolidation (VGPR / no) 0.0040.004
15. Grade 3-4 Adverse Events during
Maintenance
AEs (grade 4) Arm A Arm B
Anemia 0% 3% (2%)
Thrombocytopenia 3% 8% (3%)
Neutropenia 6% (1%) 31% (7%)
Febrile Neutropenia 0% 0.1%
Infections 4% 8%
DVT 0.3% 0.6%
Skin disorders 1% 4%
Fatigue 0.6% 2%
Peripheral Neuropathy 0.3% 0.4%
Neoplasia 0.9% 1%
Overall discontinuation due to AEs: XX % placebo versus XX % lenalidomid
16. 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
Placebo
Lenalidomide*
10 mg/d with
↑↓ (5–15 mg)
Lenalidomide*
10 mg/d with
↑↓ (5–15 mg)
RestagingRestaging
Days 90Days 90––100100
RegistrationRegistration
CALGB 100104 SchemaCALGB 100104 Schema
CR
PR
SD
Stratification based on registration β-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)
Mel 200Mel 200
ASCTASCT
* provided by Celgene
Corp, Summit, NJ
Randomization
17. ITT Analysis with a median follow-up from transplant of 34
months. P < 0.001 Estimated HR=0.48 (95% CI = 0.36 to
0.63), Median TTP: 46 months versus 27 months.
CALGB 100104, NEJM 2012
follow up to 10/31/2011
86 of 128 placebo patients
crossed over to lenalidomide
18. 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
Median follow-up of 34 months
19. 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
follow up to 10/31/2011
20. CALGB 100104, NEJM 2012
After cross over,
most placebo patients
were on lenalidomide
24. Tales of Two Cases
Case 1
• 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
• Receives 4 cycles of Bortezomib /Thal/Dex
• Followed by Auto SCT on Day 60
documented stringent CR
Case 2
• 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 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 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?
25. BMT CTN 0702 StAMINA TRIAL: A Trial of Single Autologous
Transplant with or without RVD Consolidation versus Tandem
Transplant and Maintenance Therapy.
26. BMT CTN 0702: SCHEMA
Register
and
Randomize
MEL
200mg/m2 VRD x 4*
Lenalidomide
Maintenance**
Lenalidomide
Maintenance**
Lenalidomide
Maintenance
MEL
200mg/m
2
**Lenalidomide 15 mg daily x**Lenalidomide 15 mg daily x
3years3years
* Bortezomib 1.3mg /m2 days 1,
4, 8,11
Lenalidomide 15mg days 1-15
Dexamethasone 40mg days 1,
8, 15
*
27. Monitoring Disease
CR Definition Does Matter With Regards to Depth of
Remission
Rate of molecular CR with HDT is 5%
At diagnosis
Partial response –
50% reduction in M protein
Near complete remission –
immunofixation positive only
Complete remission –
immunofixation negative
Nonquantitative ASO-PCR
Quantitative ASO-PCR
flow cytometryMRD
1 × 104
1 × 106
1 × 108
1 × 1012
Numberof
Myeloma
Cells
28. 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?
29. 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
Notas del editor
VAD-thal 16, 38, 42, 71 PAD-bortez 30, 50, 48, 78
Attal et al., ASH 09; abstract 529
We also tried to analyzed the impact of different prognostic factors to achieve VGPR after consolidation. 3 factors were significantly associated with a higher rate of VGPR: VD as induction regimen, the achievement of VGPR after induction, and one line of induction
The incidence of grade ¾ AE was acceptable: 15% Hematological 12%, allergic 3%, infection 1%, only 2 patients experienced thromboembolic events
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