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Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Treatment For Newly Diagnosed Myeloma A. Keith Stewart.

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Presentation on theme: "Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Treatment For Newly Diagnosed Myeloma A. Keith Stewart."— Presentation transcript:

1 Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Treatment For Newly Diagnosed Myeloma A. Keith Stewart

2 Risk Adapted Therapy Age Renal function Co morbid conditions Geography AccessPatient Preference Risk Profile

3 mSMART 2.0: Classification of Active MM  FISH  Del 17p  t(14;16)  t(14;20)  GEP  High risk signature All others including:  Hyperdiploid  t(11;14)***  t(6;14)  FISH  t(4;14)*  Cytogenetic Deletion 13 or hypodiploidy  PCLI >3% High-Risk 20%Intermediate-Risk 20% Standard-Risk 60% ** * Prognosis is worse when associated with high beta 2 M and anemia ** LDH >ULN and beta 2 M > 5.5 in standard risk may indicate worse prognosis *** t(11;14) is associated with plasma cell leukemia

4 Initial Therapy Considerations Ensure patient does not have smoldering (asymptomatic) MM Approach to therapy is based on whether a pt is a transplant candidate Consider clinical trials if available Improving complete response rates is a key goal of current trials

5 Clearly not a transplant candidate Can include melphalan- based combinations Potential transplant candidate Non-alkylator based induction Stem cell harvest Initial Approach to Treatment

6 Therapy Options: NonTransplant Candidate Melphalan + Prednisone (MP) Melphalan + Prednisone + Thalidomide (MPT) Melphalan + Prednisone + Bortezomib (MPV) Dexamethasone (Dex) Thalidomide + Dexamethasone (Thal/Dex) Lenalidomide + Dexamethasone (Rev/Dex) NCCN Practice Guideline-v

7 Therapies for younger patients

8 Transplant ?

9 What About Maintenance NThalidomideCR ratePFS (year)OS (year) Barlogie mg Taper 62% vs. 43% 5-year 56% vs. 44% 6-year Superior for Thal in CA abnormal Attal mg Until progression or adverse event 67% vs. 55% 4-year 52% vs. 36% 4-year 87% vs. 77% Spencer mg 12 months 63% vs. 40% 3-year 63% vs. 36% 3-year 90% vs. 81% Barlogie, Tricot, et al, 2006; Attal et al, 2003; Spencer et al, 2009.

10 IFM : Study design Arm A= Placebo (N=307) until relapse Patients < 65 years, with non-progressive disease,  6 months after ASCT in first line Arm B= Lenalidomide (N=307) mg/d until relapse Primary end-point: PFS. Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide…. Phase III randomized, placebo-controlled trial N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008 Consolidation: Lenalidomide alone 25 mg/day p.o. days 1-21 of every 28 days for 2 months Randomization: stratified according to Beta-2m, del13, VGPR

11 PFS according to Response Pre- Consolidation HR= CI 95% [ ]HR= CI 95% [ ] PR or SD VGPR or CR p<10 -5 p=0.001

12 Lenalidomide Maintenance: TTP Median Follow up from randomization is 12 months Median TTP: Not yet reached Median TTP 25.5 mos CALGB , Nov 2009

13 Palumbo et al, 2009 MPR-R vs. MPR Progression-Free Survival MPR-R MPR Median PFS Not reached 13.2 months HR PFS Time (months) Patients without Event (%)

14 How to treat standard risk disease Standard-Risk 1. OS is 80% at 5 years (before routine maintenance adopted) 2. No difference in induction regimens (needs further study) 3. A drug regimen which results in high overall response rates and which avoids extremes of toxicity (Rd, weekly bortezomib, MPT) 4. Transplant indicated in younger but may be deferred 5. Maintenance likely helps All others including:  Hyperdiploid  t(11;14)***  t(6;14)

15 How to Treat Standard Risk Disease All others including:  Hyperdiploid  t(11;14)***  t(6;14) Standard-Risk ** 150 transplant eligible standard risk patients treated with RD, CRD or CBD +/- HDM.

16 How to treat Intermediate Risk Disease  FISH  t(4;14)  Cytogenetic Deletion 13 or hypodiploidy  PCLI >3% Intermediate-Risk Bortezomib-Dex better than VAD Pre transplant

17 Short remission post transplant despite high response rates Del 17 t(4;14) All others 4 cycles of CyborD induction and high dose melphalan

18  FISH  t(4;14)*  Cytogenetic Deletion 13 or hypodiploidy  PCLI >3% Intermediate-Risk VMP standard risk (N=142): not reached (16 events) VMP high risk (N=26): not reached (3 events) Prolonged use of Bortezomib may help overcome intermediate risk

19 IFM2005: Len maintenance improves PFS even with elevated ß2-m ß2-m  3 mg/l ß2-m > 3 mg/l p=0,0002 p<10 -5 Attal et al. 2010

20 How to treat Intermediate Risk Disease Intermediate-Risk  FISH  t(4;14)*  Cytogenetic Deletion 13 or hypodiploidy  PCLI >3% 1.A bortezomib based multi-agent chemotherapy (CyborD, VRD, VTD, MPV) which maximizes CR 2.Longer duration of bortezomib 3.Autologous transplant 4.Consider Consolidation if not in CR 5.IMID based Maintenance 6.Consider targeted therapy approach on trials

21 High Risk Disease: Not very effective Velcade Dex Tandem Autologous Transplant Allogeneic Transplant Maintenance Thalidomide

22 POSSIBLY HELPFUL Chemotherapy targeting proliferation ? Longer duration bortezomib ? Lenalidomide maintenance ?

23 How to treat High risk disease  FISH  Del 17p  t(14;16)  t(14;20)  GEP  High risk signature High-Risk 1.This population needs novel ideas and therapeutic concepts 2. A multi drug regimen incorporating all available drugs which emphasizes durable CR and uses longer duration of therapy may improve outcomes for p53 deletion 3. Transplant contribution is however of dubious benefit and IMID based maintenance still uncertain

24 mSMART 2.0: Treatment of Active MM Novel approaches New drugs “TT3 like” approach for p53 deletion ? Regimen which provides a high ORR and which minimizes early toxicity HDM could be delayed in patients achieving CR Lenalidomide maintenance Prolonged Bortezomib based combination HDM +/- consolidation Lenalidomide maintenance Targeted therapy High-RiskIntermediate-Risk Standard-Risk

25 While risk adapted therapy is appealing, randomized trial data is largely lacking:  Minimize toxicity argument: High risk patients do less well even with very aggressive therapy so quality of life more important. Lower risk patients should be treated with focus on lower toxicity as survival long anyway.  Maximize therapy argument: Although less aggressive therapy for standard risk disease may result in good outcomes most patients still relapse so all deserve the most intensive therapy The Debate Will Continue


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