Maintenance Therapy in Myeloma Myeloma Canada National Conference Donna E. Reece, M.D. Princess Margaret Hospital 24 September 2011 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 May be hard to distinguish from “consolidation” therapy …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… Defined as relatively intensive, short-term post-ASCT therapy Maintenance can be used after ASCT or non-transplant therapy 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 Older maintenance trials showed limited benefit from Melphalan maintenance not effective and too hard on normal marrow 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 Maintenance after ASCT ASCT ASCT No maintenance Relapse Maintenance with drug “A” Use drug “A” Relapse ?Longest Time in Remission? ?Best Overall Survival? Use other drugs Phase III Maintenance Therapy Trials in Myeloma Thalidomide Lenalidomide 7 randomized studies Different doses and duration of thalidomide; some used steroids Different control arms 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 Thalidomide Maintenance Trials Author/Year N Thalidomide dose (mg) /duration Attal/2006 597 Thal 200 (median dose) vs obs /progression + + Spencer/2006 243 Thal 200 + pred vs pred/ 12 months + + Maiolino/2008 212 Thal 200 + dex vs dex/ 12 months + NS Barlogie/2006* 668 Thal 400/ progression + NS Thal 100/ progression +/- Morgan/2008* -- Progression- Overall free Survival Survival (+ in highrisk) NS (if optimal relapse Rx) Lokhorst/2010* 550 Thal 50/ progression + - Stewart/2010 325 Thal 200 + pred vs obs/ 48 months + NS 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 Summary of Phase III Trials of Lenalidomide Maintenance after ASCT Author/Year N Pre-ASCT induction # ASCT PFS/TTP Median (months) Attal/2010 (IFM 2005-02) 614 VAD or Velcade + dex 1 or 2 McCarthy/2010 (CALBG 100104) 568 Lenalidomide 32% Bortezomib 42% Thalidomide 16% 1 42 24 3-year (%) Lenalidomide 60%* Observation 33% 42.3 Lenalidomide ~50%* 21.8 Observation ~25% Attal M, et al. ASCO 2010; abstract #8018; McCathy PL, et al. ASCO 2010; abstract #8017. Overall Survival 3-year (%) Lenalidomide Observation 81% 81% Lenalidomide Observation ~80% ~80% 24 mo 0.00 21.9 mos 0.25 0.50 39.6 mo IFM 2005-01 42 mo 0.75 CALGB100104 1.00 Lenalidomide Maintenance Effect on PFS 0 6 12 18 Placebo Progression Free Survival (PFS) McCathy PL, et al. Haematologica 2011; 96 (Suppl 1): S23. 24 30 36 42 Revlimid Event Free Survival (EFS) Attal M, et al. ASCO 2010; abstract #8018. Lenalidomide Maintenance Overall Survival Benefit? IMF 2005-02 0.00 0.25 0.50 0.75 1.00 CALGB 100104 0 6 12 18 Placebo Median follow-up of 28 mos. P=0.018 McCathy PL, et al. Haematologica 2011; 96 (Suppl 1): S23. 24 30 36 Revlimid No significant difference Attal M, et al. ASCO 2010; abstract #8018. 42 Significant Toxicity with Lenalidomide Maintenance Phase III Trials Toxicity IMF 2005-02 CALGB Len Placebo Len Placebo Low neutrophils (WBC) 43% 14% 43% 9% Low platelets 12% 6% 13% 4% Fever + low WBC 2% 0.1% 6% 2% Documented Infection 10% 4% 16% 5% Discontinuation of lenalidomide 6% 4% 13% 2% N=23 (6.8%) N=6 (1.6%) N=18 (6.5%) N=4 (2.6%) 2º malignancy Attal M, et al. ASCO 2010; abstract #8018; McCarthy PL, et al. ASCO 2010; abstract #8017; Attal M, personal communications; IMWG Feb 2011. Secondary Cancers with Lenalidomide Maintenance: Considerations Small increase in incidence, but..... No increase when lenalidomide used for relapsed myeloma Other drugs/agents may predispose to second cancers IFM study counted skin cancers CALGB study had several cases even before starting drug 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! Future Directions and Answers: CTN Trial VRD x 3 Melphalan 200 mg/m2 + ASCT SC collection CY + G-CSF Melphalan 200 mg/m2 + ASCT Melphalan 200 mg/m2 + ASCT Len maintenance Melphalan 200 mg/m2 + ASCT VRD consolidation Randomized Trial VAD +Thalidomide Maintenance vs Bortezomib in Induction and Maintenance Phase III Trial of VAD or PAD Induction with Thalidomide vs Bortezomib Maintenance: HOVON MM 65/GMMG-HD4 PFS 3-year PFS 48% vs 42% Sonneveld P, et al. ASH 2010: abstract 40. Overall Survival 3-year OS 78% vs 71% 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