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