The evidence supporting continuous therapy in multiple myeloma

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. 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. 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.

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. 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. 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. 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. Impact of thalidomide based maintenance post-ASCT • 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 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].

9. Impact of bortezomib and thalidomide maintenance post-ASCT HOVON-65/GMMG-HD4 trial Years (%) * Patients received one (HOVON) or two (GMMG) treatments with high-dose melphalan (HDM) with ASCT. Sonneveld P, et al. Blood. 2010;116:[abstract 40].

10. Tales of Two Cases Case 1 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 • 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

11. Phase III IFM 2005-02: Lenalidomide as Consolidation/Maintenance Post-ASCT Maintenance Consolidation Lenalidomide: 25 mg/d Days 1–21/month 2 months Lenalidomide: 10–15 mg/d until relapse N = 614 First-line ASCT < 65 years ≤ 6 months No PD Lenalidomide: 25 mg/d Days 1–21/month 2 months Placebo until relapse Primary end point: PFS Attal et al, 2009.

12. IFM 2005-02 : PFS from randomization .

13. PFS according to Response Pre-Consolidation VGPR or CR PR or SD Len Len Placebo Placebo p<10-5 p=0.001 HR= 0.37 - CI 95% [0.25-0.58] HR= 0.54 - CI 95% [0.37-0.78]

14. IFM 2005 02 : Prognostic factors for PFS

15. Grade 3-4 Adverse Events during Maintenance Overall discontinuation due to AEs: XX % placebo versus XX % lenalidomide

16. CALGB 100104 Schema Registration Restaging Days 90–100 Randomization Mel 200 ASCT Placebo 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 CR PR SD Lenalidomide* 10 mg/d with ↑↓ (5–15 mg) * provided by Celgene Corp, Summit, NJ 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)

17. 86 of 128 placebo patients crossed over to lenalidomide CALGB 100104, NEJM 2012 follow up to 10/31/2011 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.

18. Median follow-up of 34 months 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

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. After cross over, most placebo patients were on lenalidomide CALGB 100104, NEJM 2012

21. 100104: NEJM 2012

22. CALGB 100104, NEJM 2012

23. CALGB 100104, NEJM 2012

24. Tales of Two Cases Case 1 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 • 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 • THEY BOTH ASK • Should they get consolidation? • Should they get a 2nd SCT? • Should they receive post transplant lenalidomide?

25. BMT CTN 0702 StAMINA TRIAL: A Trial of Single Autologous Transplant with or without RVD Consolidation versus Tandem Transplant and Maintenance Therapy.

26. BMT CTN 0702: SCHEMA Lenalidomide Maintenance * Registerand Randomize MEL 200mg/m2 Lenalidomide Maintenance** VRD x 4* MEL 200mg/m2 Lenalidomide Maintenance** * Bortezomib 1.3mg /m2 days 1, 4, 8,11 Lenalidomide 15mg days 1-15 Dexamethasone 40mg days 1, 8, 15 **Lenalidomide 15 mg daily x 3years

27. Monitoring DiseaseCR Definition Does Matter With Regards to Depth of Remission 1 × 1012 At diagnosis Number ofMyelomaCells Partial response – 50% reduction in M protein Near complete remission – immunofixation positive only Complete remission – immunofixation negative Nonquantitative ASO-PCR 1 × 108 Quantitative ASO-PCRflow cytometry 1 × 106 MRD 1 × 104 Rate of molecular CR with HDT is 5%

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. 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