The evidence supporting continuous
therapy in multiple myeloma
Sergio Giralt, MD
Chief, Adult Bone Marrow Transplant Servi...
Why Maintenance Therapy?
• Induction therapy followed by autologous SCT alone will
cytoreduce but not cure most Multiple M...
Maintenance Therapy
Philosophical Perspective
• Pros
• Increases remission duration.
• Maintains minimal disease
burden pr...
Rationale for continuous treatment in the
era of IMID’s and Proteosome Inhibitors
• Primary therapy even with high dose th...
Potential risks of continuous treatment in
the era of IMID’s and Proteosome Inhibitors
• Adverse events related to long-te...
Historical Perspective
• Long term alkylator therapy associated with higher risk
of 2ry MDS/AML
• Interferon maintenance m...
Upgrade in MRD negativity with
consolidation: GIMEMA study
• VTD compared with TD consolidation (x 2 cycles
starting withi...
Patients
(N)
Duration of treatment CR + VGPR (%) EFS or PFS (%) OS (%)
TT21,2
668 Double ASCT
Thal vs no maintenance
until...
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-
maintenan...
Tales of Two Cases
Case 1
• 55 yo female presents with
asymptomatic anemia of 10 gm/dl
and total serum protein 10 gm/lt
• ...
Phase III IFM 2005-02: Lenalidomide asPhase III IFM 2005-02: Lenalidomide as
Consolidation/Maintenance Post-ASCTConsolidat...
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...
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 ...
IFM 2005 02 : Prognostic factors for PFS
Univariate analysisUnivariate analysis pp
AgeAge NSNS
ISS (I / II + III)ISS (I / ...
Grade 3-4 Adverse Events during
Maintenance
AEs (grade 4) Arm A Arm B
Anemia 0% 3% (2%)
Thrombocytopenia 3% 8% (3%)
Neutro...
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/...
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), Me...
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....
The cumulative incidence risk of second primary cancers was greater in the
lenalidomide group (P=0.0008). The cumulative i...
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
• 55 yo female presents with asymptomatic
anemia of 10 gm/dl and total serum protein
10 gm/lt
• ...
BMT CTN 0702 StAMINA TRIAL: A Trial of Single Autologous
Transplant with or without RVD Consolidation versus Tandem
Transp...
BMT CTN 0702: SCHEMA
Register
and
Randomize
MEL
200mg/m2 VRD x 4*
Lenalidomide
Maintenance**
Lenalidomide
Maintenance**
Le...
Monitoring Disease
CR Definition Does Matter With Regards to Depth of
Remission
Rate of molecular CR with HDT is 5%
At dia...
Common Sense Scenarios
• We may never have randomized data to guide us for
all possible scenarios so clinical judgement is...
Conclusions
• Continuous treatment strategies are being evaluated in
all phases of myeloma disease from smouldering
myelom...
Upcoming SlideShare
Loading in …5
×

MAINTENANCE THERAPY IN MULTIPLE MYELOMA

1,856 views

Published on

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
1,856
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
55
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • 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 :
  • MAINTENANCE THERAPY IN MULTIPLE MYELOMA

    1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 20. CALGB 100104, NEJM 2012 After cross over, most placebo patients were on lenalidomide
    21. 21. 100104: NEJM 2012
    22. 22. CALGB 100104, NEJM 2012
    23. 23. CALGB 100104, NEJM 2012
    24. 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. 25. BMT CTN 0702 StAMINA TRIAL: A Trial of Single Autologous Transplant with or without RVD Consolidation versus Tandem Transplant and Maintenance Therapy.
    26. 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. 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. 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. 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

    ×