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
Editor's Notes
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
Curatio Fact Check : Query: Please provide citation for this figure **PERMISSION REQUIRED FOR HANDOUT AND WEB ENDURING** Abbrevs :
