1. Review Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement Presenter:R4 劉耀中 醫師 Supervisor : 高志平 醫師 Aug 15, 2011,VGH Leukemia (2011) 25, 749–760; doi:10.1038/leu.2011.3; published online 4 February 2011 財團法人台灣癌症臨床研究發展基金會

2. Outline  Brief introduction  Optimal timing and duration of the therapy  Use in special populations  Prevention and management of adverse events  Consensus summary

3. About multiple myeloma  Thalidomide, lenalidomide and bortezomib  positive effect on survival in MM.  Treatment goal: the best possible response with cytoreductive therapy or sustainment of disease control.  Lenalidomide: direct tumoricidal and immunomodulatory effects  quality of response, and prolong the time to relapse and OS.

4. Richardson P et al. Blood 2009;114:772-778 ©2009 by American Society of Hematology Mechanism of lenalidomide

5. Treatment response  Monotherapy of Len.: moderately active in relapsed or refractory multiple myeloma (RRMM). Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood 2009  Superior efficacy in Len/Dex for least one previous therapy (Table 1).Table 1  Approval of lenalidomide on the results of two multicenter, randomized, placebo-controlled trials comparing Len/Dex with placebo/Dex in patients with RRMM. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007

6. Approval of Len/Dex 13.5 months 4.7 months 13.5 months 8.4 months 4.7 months 4.6 months Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007

7. Subgroup analysis of Len/DEx

10.  In light of these emerging data, there is a need for refinement of the recommendations regarding the optimal use of Len/Dex in daily practice.  In July 2010, an expert panel convened in Munich, Germany, to discuss the available data and provide practical recommendations.  The following report summarizes the key points on which the expert panel reached a consensus regarding the use of lenalidomide in RRMM.

11. Outline  Brief introinduction  Optimal timing and duration of the therapy  Use in special populations  Prevention and management of adverse events  Consensus summary

12. What is the optimal time to initiate Len/Dex in relapsing patients?  More effective at first relapse J Haematol 2009; 82: 426–432 Stadtmauer EA, Weber DM, Niesvizky R, Belch A, Prince MH, San Miguel JF et al. Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma. Eur

13. What is the optimal time to initiate Len/Dex in relapsing patients? Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 2008

14. What is the optimal time to initiate Len/Dex in relapsing patients?  In VISTA trial: effective at first relapse who had or had not received bortezomib as a part of the first-line therapy. VISTAL trial: Mateos MV et al. J Clin Oncol 2010; 28: 2259–2266  High-dose chemotherapy and ASCT does not appear to affect the efficacy of Len/Dex Reece D et al. Blood 2009; 114: 522–525.  Advanced age, poor performance status, IgA-type disease and advanced disease stage: not influenced Lonial S, et al.. Haematol 2007; 92  The efficacy in pts with/without RI and neuropathy: comparable Delforge M et al. Blood 2009; 114:

15. Consensus panel opinion  Len/Dex is most effective when used at first relapse.  Len/Dex can be administered regardless of the type of previous therapy.

16. What is the optimal starting dose of Len. when combined with Dex.?  25 mg once daily orally on days1–21 of each 28-day cycle.  Based on two key factors: renal function and the presence of cytopenias at baseline

17. What is the optimal starting dose of Len. when combined with Dex.?  Is G-CSF used concomitantly or very soon after treatment initiation?  a short course of G-CSF (3 days) in certain cases, such increased bone marrow infiltration. Mateos MV et al. Should prophylactic granulocyte-colony stimulating factor be used in multiple myeloma patients developing neutropenia under lenalidomide-based therapy? Br J Haematol 2008; 140: 324–326

18. Consensus panel opinion  For renal impairment and cytopenia, the starting dose of Len. should be reduced, depending on the degree of impairment.

19. What is the optimal starting dose of dexamethasone?  Len/Dex regimen, use of a lower total dose of dexamethasone: 1. Reduction in serious adverse events and early deaths, particularly within the first 4 months, in newly diagnosed MM. Rajkumar SV et al. Lancet Oncol 2010; 11: 29–37 2. Dex. enhances the tumoricidal effects of lenalidomide but partly antagonizes its immunomodulatory effects, Gandhi AK, et al. Curr Cancer Drug Targets 2010; 10: 155–167. 3. Association with improved tolerability and efficacy. 4. Standard, high-dose dexamethasone for certain cases, such as cord compression, hypercalcemia or renal failure. European Medicines Agency evlimid. Available from: http://www.emea.europa.eu. Accessed July 2010http://www.emea.europa.eu

20. High dose VS. low dose Dex. Rajkumar SV et al. Lancet Oncol 2010; 11: 29–37

21. Recommendations on Dex. dose

22. Consensus panel opinion  Low-dose Dex./Len. : better tolerability without loss of efficacy.  The recommended dose of Dex./ Len. according to age in patients with RRMM is shown in Table 3.

23. What is the optimal duration of Len/Dex therapy?  In MM-009/010, study treatment continued until progression or unacceptable toxicity. Dimopoulos M,. N Engl J Med 2007  50% of patients with initial PR later achieved a CR or VGPR and better longer median TTP and OS with continued treatment. Harousseau JL, et al.. Haematologica 2010; 95: 1738–1744.  Continuous therapy has a lower risk of death. San Miguel JF, et al.. Clinl Lymphoma Myeloma Leuk 2010; E-pub ahead of print 26 October 2010  Lenalidomide maintenance therapy after ASCT or as a continuous therapy: prolong TTP Attal M, et al. J Clin Oncol (ASCO Ann Meet Proc) 2010; 28

24. Copyright ©2010 Ferrata Storti Foundation Harousseau, J.-L. et al. Haematologica 2010;95:1738-1744 Figure 1. Accumulated maximum serum M-protein reduction after lenalidomide plus dexamethasone by treatment cycle for all patients achieving at least a partial response as best response Figure 2. Cumulative response by treatment cycle for patients with complete response (CR)/very good partial response (VGPR) to lenalidomide plus dexamethasone (n=114) ‏

25. Consensus panel opinion  Len/Dex may continue in responding patients until evidence of disease progression.  Treatment should continue at the best- tolerated dose of each agent.  Caution with long-term dexamethasone use is required.

26. How often should patients be monitored during therapy? Consensus panel opinion:  Pts without cytopenias may be monitored every 2 wks for the first C2–3.  Pts with neutropenia or thrombocytopenia may require more intensive monitoring.  For continuous Len/Dex, monitoring at the start of each new treatment cycle.  Pts with RI may require more intensive monitoring.

27. Outline  Brief introinduction  Optimal timing and duration of the therapy  Use in special populations  Prevention and management of adverse events  Consensus summary

28. Advanced age  Pts into three groups ( 75 years), comparing Len/Dex with Dex alone: 1. RR to Len/Dex: similar in three groups and higher than Dex alone. 2. Median TTP: higher in Len/Dex than in Dex alone. Consensus panel opinion: Len/Dex is an appropriate treatment option for patients with RRMM, regardless of age. Lonial S, et al. Effect of Len/Dex in MM in different age groups. Haematol (EHA Annu Meet Abstr) 2007; 92(Suppl 2): (abstract PO-663).

29. Renal impairment  In MM-009/010 study, pts with SCr>2.5mg/dl were excluded.  When assessed by CCr, however, 82 pts (24%) treated with Len/Dex were deemed to have moderate RI (CCr 30– 60 ml/min) and 16 patients (5%) had severe RI (CCr <30 ml/min) at baseline. Dimopoulos M, et al. The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function. Cancer 2010; 116: 3807–3814.

30. OS in severe RI: 18.4m in moderate RI: 29.0m in mild or no RI: 38.9m

31. Consensus panel opinion  Len/Dex is safe and effective in patients with RI, provided that the dose of lenalidomide is adjusted appropriately according to the creatinine clearance at each cycle.

32. Cytogenetic abnormalities  Cytogenetic abnormalities such as del(13q), t(4;14) and del(17p): poor prognostic factors in MM  ongoing research with novel agents  Reece et al : RR and OS in Len/Dex with del(13q) and t(4;14) were similar to normal pts. (Pts with del(17p): worse than those without del(17p)) Reece D,et al. Blood 2009; 114: 522–525

33. Reece D,et al. Blood 2009; 114: 522–525

34. Cytogenetic abnormalities  Avet-Loiseau et al.: PFS and OS with del(13q) and t(4;14) were lower. Results according to del(17p) status could not be evaluated because of the low number of patients with del(17p) (n=8). Avet-Loiseau H, et al. Leukemia 2010; 24: 623–628.

35. Cytogenetic abnormalities  OR and survival outcomes were lower in those with del(13q), del(17p), t(4;14) and amp(1q21). Dimopoulos MA, et al. Leukemia 2010; 24: 1769–1778.  Response rates were similarly high in high-risk and standard-risk patients (81 and 89%; P=0.56), but median PFS was lower in high- risk patients (18.5 vs 36.5 months; P<0.001). Moreau P et al. Leukemia 2007; 21: 2020–2024  Novel combinations of lenalidomide and bortezomib : overcome the negative effects of certain cytogenetic abnormalities. (but del(17p) remains poor) Richardson P et al. Blood (ASH Annu Meet Abstr) 2008; 112

36. Consensus panel opinion  More data are needed before definitive recommendations can be made regarding the influence of cytogenetic abnormalities on the efficacy of Len/Dex.  Enrollment in a clinical trial is recommended for patients with del(17p).

37. Outline  Brief introinduction  Optimal timing and duration of the therapy  Use in special populations  Prevention and management of adverse events  Consensus summary

38. Myelosuppression  In MM-009/010, neutropenia occurred early in the course of treatment: the most severe within 6 months (52%) and within 12 months (76%) Lonial S, et al.. Blood (ASH Annu Meet Abstr) 2009; 114

39. Consensus panel opinion  Neutropenia and thrombocytopenia often occur in patients treated with Len/Dex, but are predictable and manageable.  Neutropenia can be managed with a combination of growth factor support, lenalidomide dose modifications or discontinuation.  Thrombocytopenia can be managed with a combination of platelet transfusions, lenalidomide dose modifications or discontinuation.

40. Venous thromboembolism  The risk of VTE is low as monotherapy with Len., but increases in Len/Dex in elderly patients. Rajkumar SV,et al.. Lancet Oncol 2010; 11: 29–37  Concomitant use of EPO increase the risk of VTE Rizzo JD,et al. J Clin Oncol 2008; 26: 132–149  VTE in MM-009/010 was 16% : thromboprophylaxis was not a requirement. Dimopoulos M,. N Engl J Med 2007  Prophylaxis with LMWH or low-dose aspirin effectively reduces VTE to 2–5%. Klein U, et al.. Ann Hematol 2009; 88: 67–71.  In previously untreated pts, aspirin prophylaxis: reduce the risk of VTE from 75% (9 of 12 patients) to 15% (4 of 26 patients). Zonder JA, et al. Blood 2006; 108: 403

41. Venous thromboembolism a.High risk includes immobilization and previous history.

42. Consensus panel opinion  Thromboprophylaxis for pts with Len/Dex.  Aspirin for standard risk; LMWH for higher risk  LMWH prophylaxis should continue for at least the first four cycles and then switch to aspirin.  Prophylaxis for the entire duration of treatment  Len/Dex should be resumed in pts considered stable on anticoagulation therapy.

43. Rash  Rash has been reported in 16% of pts and more likely occurrs during the first cycle. Dimopoulos M,. N Engl J Med 2007  Consensus panel opinion: 1. Antihistamines and topical steroids can use. 2. Len. discontinue permanently in pts with diffuse, desquamating, exfoliative or bullous rash.

44. Other adverse events  Infection was reported in 14% of pts in MM-009/010 Dimopoulos M,. N Engl J Med 2007  Muscle cramps was reported in 30% pts. European Medicines Agency. Available from: http://www.emea.europa.eu. Accessed July 2010http://www.emea.europa.eu  Dexamethasone-related myopathy, chronic non- neutropenic infections, fatigue, psychological changes or hyperglycemia.

45. Outline  Brief introinduction  Optimal timing and duration of the therapy  Use in special populations  Prevention and management of adverse events  Consensus summary

46. Consensus summary  Len/Dex. is an effective and well-tolerated treatment option for RRMM.  Use as early lines of MM therapy and continue until disease progression.  In responding/stable pts, continuing Len/Dex is associated with further improvement in the quality of response and improved outcomes.  Effective and safely in pts with RI (adjusted dose).  Independent factor: age, PS and disease stage.

47. Consensus summary  Resistance to previous MM therapies reduces response to Len/Dex.  More data are needed to determine the efficacy in pts with cytogenetic abnormalities  VTE can be minimized with proper prophylaxis, particularly in high-risk  Neutropenia and thrombocytopenia can be managed (G-CSF support, platelet transfusions).  Further, in pts with RRMM, Len/Dex is most effective when administered at first relapse as a continuous long-term treatment

48. Thank you for your listening