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The evidence supporting continuous therapy in multiple myeloma
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Transcript of The evidence supporting continuous therapy in multiple myeloma
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 TherapyPhilosophical 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.
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].
Patients (N)
Duration of treatment CR + VGPR (%) EFS or PFS (%) OS (%)
TT21,2 668 Double ASCTThal 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 ASCTPam + 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 ASCTPred + 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 maintenanceuntil progression
NA HR: 1.36; 95% CI: 1.15–1.61p < 0.001
NS
Lokhorst6 556 Double or single ASCTThal vs alpha-interferon
until progression
66 vs 54p = 0.005
34 vs 22p < 0.001
73 vs 60p = 0.77
Stewart7 332 Single ASCTThal + Pred vs observation
until progression
Not reported 28 months vs 17 months
p < 0.0001
Median not reached vs 5 yearsP = 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
Impact of bortezomib and thalidomide maintenance post-ASCT
16
3842
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-thalidomidePAD-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.
Yea
rs (
%)
HOVON-65/GMMG-HD4 trial
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
Phase III IFM 2005-02: Lenalidomide as Phase 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/month2 months
Primary end point: PFS
≤ 6 monthsNo PD
N = 614
Lenalidomide: 10–15 mg/duntil relapse
Lenalidomide: 25 mg/d Days 1–21/month2 months
Placebo until relapse
Consolidation
Attal et al, 2009.
IFM 2005-02 : PFS from randomization
. Arm A
N=307
Arm B
N=307P
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
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
0.00
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36
Placebo Revlimid
0.00
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36
Placebo Revlimid
p<10-5 p=0.001
Placebo
Placebo
Len
Len
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
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 % lenalidomide
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)
RestagingRestagingDays 90Days 90––100100
RegistrationRegistration
CALGB 100104 SchemaCALGB 100104 Schema
CRPRSD
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)
Mel 200Mel 200
ASCTASCT
* provided by Celgene Corp, Summit, NJ
Randomization
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 2012follow up to 10/31/2011
86 of 128 placebo patients crossed over to lenalidomide
CALGB 100104, NEJM 2012follow 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
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 2012follow up to 10/31/2011
CALGB 100104, NEJM 2012
After cross over,most placebo patientswere on lenalidomide
100104: NEJM 2012
CALGB 100104, NEJM 2012
CALGB 100104, NEJM 2012
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 ASK1)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
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
*
Monitoring DiseaseCR 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-PCRflow cytometryMRD
1 × 104
1 × 106
1 × 108
1 × 1012N
um
ber
of
Mye
lom
aC
ells
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