1. Maintenance Therapy in Myeloma Myeloma Canada National Conference Donna E. Reece, M.D. Princess Margaret Hospital 24 September 2011

2. Maintenance Therapy in Myeloma  Older term derived from childhood acute leukemia therapy  In the past, most cancers not treated with maintenance  “Maintenance” therapy defined as  …any treatment administered after the completion of induction therapy in patients whose disease is either responsive or non-progressive at that time, with the goal of prolonging survival…  May be hard to distinguish from “consolidation” therapy  Defined as relatively intensive, short-term post-ASCT therapy  Maintenance can be used after ASCT or non-transplant therapy

3. Maintenance Therapy in Myeloma  Maintenance therapy has been tried in myeloma in previous years  BUT we only had melphalan, steroids and VAD as anti-myeloma tools  Melphalan maintenance not effective and too hard on normal marrow  Older maintenance trials showed limited benefit from  Interferon  Steroids  What has changed?  Availability of more effective myeloma drugs  Availability of oral drugs  Better understanding of side-effects and their management  Weekly and/or subcutaneous bortezomib

4. Maintenance after ASCT ASCT No maintenance ?Longest Time in Remission? ?Best Overall Survival? Relapse Use drug “A” ASCT Maintenance with drug “A” Relapse Use other drugs

5. Phase III Maintenance Therapy Trials in Myeloma  Thalidomide  7 randomized studies  Different doses and duration of thalidomide; some used steroids  Different control arms  Lenalidomide  2 randomized trials of low-dose lenalidomide 10 mg/day  One gave 2 months of “consolidation” with full-dose lenalidomide first  Bortezomib  2 randomized trials  One used bortezomib before ASCT as well  Second is in progress

6. Thalidomide Maintenance Trials Author/YearNThalidomide dose (mg) /duration Progression- free Survival Overall Survival Attal/2006597Thal 200 (median dose) vs obs /progression ++ Spencer/2006243Thal 200 + pred vs pred/ 12 months ++ Maiolino/2008212Thal 200 + dex vs dex/ 12 months +NS Barlogie/2006*668Thal 400/ progression + NS (+ in high- risk) Morgan/2008*--Thal 100/ progression +/- NS (if optimal relapse Rx) Lokhorst/2010*550Thal 50/ progression+- Stewart/2010325Thal 200 + pred vs obs/ 48 months +NS

7. Thalidomide Maintenance Trials: Summary  Thalidomide maintenance prolongs PFS  BUT peripheral neuropathy and other side-effects limit the dose and duration of maintenance  Quality of life negatively impacted  Benefit on survival variable  Most patients cannot tolerate it much beyond a year  Likely in part related to availability of “good” therapy when the disease progresses

8. Summary of Phase III Trials of Lenalidomide Maintenance after ASCT Author/YearNPre-ASCT induction# ASCTPFS/TTP Median 3-year (months) (%) Overall Survival 3-year (%) Attal/2010 (IFM 2005-02) 614VAD or Velcade + dex 1 or 242 Lenalidomide 60%* 24 Observation 33% Lenalidomide 81% Observation 81% McCarthy/2010 (CALBG 100104) 568 Lenalidomide 32% Bortezomib 42% Thalidomide 16% 142.3 Lenalidomide ~50%* 21.8 Observation ~25% Lenalidomide ~80% Observation ~80% Attal M, et al. ASCO 2010; abstract #8018; McCathy PL, et al. ASCO 2010; abstract #8017.

9. Lenalidomide Maintenance Effect on PFS 39.6 mo 21.9 mos CALGB100104 IFM 2005-01 42 mo 24 mo Progression Free Survival (PFS) Event Free Survival (EFS) Attal M, et al. ASCO 2010; abstract #8018.McCathy PL, et al. Haematologica 2011; 96 (Suppl 1): S23.

10. Lenalidomide Maintenance Overall Survival Benefit? CALGB 100104IMF 2005-02 Median follow-up of 28 mos. P=0.018 No significant difference Attal M, et al. ASCO 2010; abstract #8018.McCathy PL, et al. Haematologica 2011; 96 (Suppl 1): S23.

11. Significant Toxicity with Lenalidomide Maintenance Phase III Trials ToxicityIMF 2005-02CALGB LenPlaceboLenPlacebo Low neutrophils (WBC) 43%14%43%9% Low platelets12%6%13%4% Fever + low WBC2%0.1%6%2% Documented Infection 10%4%16%5% Discontinuation of lenalidomide 6%4%13%2% 2º malignancyN=23 (6.8%) N=6 (1.6%) N=18 (6.5%) N=4 (2.6%) Attal M, et al. ASCO 2010; abstract #8018; McCarthy PL, et al. ASCO 2010; abstract #8017; Attal M, personal communications; IMWG Feb 2011.

12. Secondary Cancers with Lenalidomide Maintenance: Considerations  Small increase in incidence, but.....  IFM study counted skin cancers  CALGB study had several cases even before starting drug  No increase when lenalidomide used for relapsed myeloma  Other drugs/agents may predispose to second cancers  Prolonged oral alkylating agents  XRT  Other chemotherapy drugs  Plasma cell disorders themselves have a slightly higher risk of leukemia  AWARENESS and monitoring  Myeloma is the main wolf barking at the door!

13. VRD x 3 SC collection CY + G-CSF Melphalan 200 mg/m 2 + ASCT VRD consolidation Len maintenance Melphalan 200 mg/m 2 + ASCT Melphalan 200 mg/m 2 + ASCT Melphalan 200 mg/m 2 + ASCT Future Directions and Answers: CTN Trial

14. Randomized Trial VAD +Thalidomide Maintenance vs Bortezomib in Induction and Maintenance

15. Phase III Trial of VAD or PAD Induction with Thalidomide vs Bortezomib Maintenance: HOVON MM 65/GMMG-HD4 PFS Overall Survival Sonneveld P, et al. ASH 2010: abstract 40. 3-year PFS 48% vs 42% 3-year OS 78% vs 71%

16. Maintenance Therapy in Myeloma Summary and Conclusions  Median PFS after ASCT has improved without maintenance using better induction  Maintenance with novel agents further improves PFS  Toxicity issues are critical  PFS is 3 ½ years with lenalidomide maintenance  Overall survival results are improved in some studies of thalidomide, lenalidomide and bortezomib maintenance  Bortezomib maintenance under further investigation  Decisions regarding maintenance will be influenced by  Incidence of toxicity such as 2º cancers  Outcome after myeloma progression  Identification of subgroups most likely to benefit  Funding