High-risk smoldering myeloma

1. High-risk smoldering myeloma Philippe Moreau, Nantes

2. Rajkumar et al. Lancet Oncology 2014; 15:e538-548. October

3. BEFORE… MGUS SYMPTOMATIC INDOLENT Treatment required

5. ≥60% plasma cells in bone marrow biopsies - Ultra-high risk SMM - • Biomarker validated in two independent series 1,2 634 pts “In these patients (3,2%), median TTP was 7m and 95% of them progressed to symptomatic MM within 2y” 1 21 pts • Rajkumar SV et al. N Engl J Med 2011; 365:474-475 • Kastritis E, et al. Leukemia. 2013 Apr;27(4):947-53

6. Free-Light Chain (FLC) ratio ≥100 - Ultra-high risk SMM - • Biomarker validated in three independent series 1-3 TTP: 15 m TTP: 55 m • Rajkumar SV et al. N Engl J Med 2011; 365:474-475 • Kastritis E, et al. Leukemia. 2013 Apr;27(4):947-53 • Waxman AJ, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8607)

7. >1 focal lesion by MRI - Ultra-high risk SMM - • Biomarker validated in two independent series 1,2 ≤ 1 1.0 > 1 0.8 Median TTP: NR Median TTP: NR 0.6 Progression-free survival 0.4 Median TTP: 13 months 0.2 Median TTP: 13 m Log-rank P < .001 0 0 6 12 18 24 30 36 42 48 54 60 Time Since MRI Treatment (months) • Hillengass J, et al. J Clin Oncol 2010;28:1606-1610 • Kastritis E, et al. Leukemia. 2013 Apr;27(4):947-53

8. AFTER… Treatment required MGUS SYMPTOMATIC INDOLENT MRI > 1 lesions 60% plasma cells FLC ratio > 100

9. Risk of overtreatment ? 60% of plasma cells: 3% of patients with SMM; 95% progressed within 2 years Free light chain ratio > 100: - 7-15% of pts with SMM; 64-82% progressed within 2 years MRI > 1 lesion: - 15% of patients with SMM; 70% progressed with 2 years

10. Risk of overtreatment ? 60% of plasma cells: 3% of patients with SMM; 95% progressed within 2 years Free light chain ratio > 100: - 7-15% of pts with SMM; 64-82% progressed within 2 years MRI > 1 lesion: - 15% of patients with SMM; 70% progressed with 2 years YES, IN 20 - 30% OF PATIENTS

11. Prof San Miguel :NO treatment due to the risk of overtreating 20 - 30% .................. can justify the risk of undertreating 70% of patients ??

12. N Engl J Med 369;5 august 1, 2013

13. 119 patientshigh-risk SMM Control (n = 61) Treatment(n = 57) Lenalidomide 25 mg/d, 21/28 Dexamethasone 20 mg D1-D4 et D12-D15 Induction 9 cycles (28 days) No treatment Lenalidomide 10 mg/d, 21/28 In case of asymptomatic biologic progression Dex 20 mg D1-D4 Maintenance (up to 2 years) No treatment Until symptomatic disease

15. !! Be cautious Not powered for OS Addition of dex at the time of biological progression in the Len arm vs not: PD could be masked Treatment in the control arm not defined: bias in favor of treatment group ? Patients identified as high risk using criteria other than those used in the Spanish trial would benefit in a similar manner from therapy (i.e. FLC ratio > 100, 60% plasma cells, MRI / PET lytic lesions) ??? … »results need to be reproduced by other studies »… (Rajkumar, Landgren & Mateos; Blood. 2015;125(20):3069-3075)

16. Manansach et al. Haematologica 2014

19. If we are removing the early myeloma from SMM : what is left ??CONSENSUS ON HIGH-RISK SMM ?! What is the new definition of high-risk SMM ?

21. MGUS/SMM/MM: diagnostic criteria Smouldering Multiple Myeloma (SMM) Monoclonal Gammopathy of uncertain significance (MGUS) Multiple Myeloma 3 g/dL serum • AND/OR • 10-60% • AND • Absent Present(serum/urine) AND > 10% AND Present < 3 g/dL serum AND < 10% AND Absent Monoclonal component Bone Marrow Plasma Cells (%) Myeloma defining-event Rajkumar SV. Lancet Oncology 2014

25. 77 patients SMM Overall agreement : 22 / 77 : 28.6% only

28. Del(17p), t(4;14), and +1q21 predict progression from smoldering to symptomatic MM (n=248) • del(17p13), t(4;14), +1q21 showed significant impact on TTP • Multivariate analysis: t(4;14), +1q21, HD, reduction of uninvolved immunoglobulins and risk score defined by Kyle et al. as independent factors for adverse outcome • Conclusion: specific chromosomal aberrations drive transition from asymptomatic to symptomatic disease Neben et al. JCO 2013; October 21 Epub ahead of print

29. PET-CT in SMM patients as predictor of progression to symptomatic MM (n: 120) Relative risk of skeletal progression was 3.0 (95% CI 1.3-12, P= 0.013) 16% of patientshad PET positive: 56% of themhad 1 FL with a median PET SUV of 4.45 and no osteolysiswasobserved. Median TTP:1,1 yrs Zamagni E et al. Leukemia 2016

30. Ultra-highrisk SMM: peripheralblood plasma cellcirculating(>5x106/L and/or 5% per 100 cytoplasmicIg-positive PB mononuclear cells) 14 pts (15%) 77 pts (85%) Bianchi et al. Leukemia 2013;27: 680-5

31. Gene Expression Profiling of purified CD138+ tumor cells in SMM an (n: 105) Thevalidated 70-gene model (GEP-70) identified SMM patientswith GEP70>-0.26with a 51% of progressionrisk at 2 yrs. A gene signaturederivedfrom4 genes at anoptimalbinarycut-point of 9.28, identified 14 patients (13%) with a 2-year therapyrisk of 85.7% Dhodapkar MV et al. Blood 2013 Khan RC et al. Haematologica 2015

32. Recommended work up at baseline in patients with Smouldering MM Mateos MV et al. Current hematologic malignancy reports. 2013; 8(4): 270-6.

33. SmolderingMultipleMyeloma Smoldering MM Stratificationaccordingtotherisk of progression Low/Intermediaterisk High risk Ultra highrisk Closefollow-up Candidatestoclinicaltrialstobetterknowthedisease Follow-up as MGUS MultipleMyeloma

34. SmolderingMultipleMyeloma Smoldering MM Stratificationaccordingtotherisk of progression Low/Intermediaterisk High risk Ultra highrisk Closefollow-up Candidatestoclinicaltrialstobetterknowthedisease Follow-up as MGUS MultipleMyeloma

35. SmolderingMultipleMyeloma Smoldering MM Stratificationaccordingtotherisk of progression Low/Intermediaterisk High risk Ultra highrisk Closefollow-up Candidatestoclinicaltrialstobetterknowthedisease Follow-up as MGUS MultipleMyeloma

36. Current Studies in High-Risk Smoldering MM 1. ClinicalTrials.gov. NCT01169337.2. ClinicalTrials.gov. NCT01441973.3. ClinicalTrials.gov. NCT01484275. 4. ClinicalTrials.gov. NCT01302886.5. ClinicalTrials.gov. NCT01572480. • Biomarker study of elotuzumab (phase II)[2] • Siltuximab (anti IL6) or no treatment (phase II)[3] • Biomarker study of BHQ880 (anti DKK1) (phase II)[4]: Data presented at ASH2012: no antitumor effect but anabolic activity • Lenalidomide or observation (phase III)[1] • Elotuzumab-Lenalidomide-dex • Daratumumab single agent at different doses (Centaurus trial) • Carfilzomib, lenalidomide, and dexamethasone (phase II)[5]:

37. Phase II trial for high-risk SMM: Carfilzomib/Revlimid/dex Study open for high-risk smoldering myeloma pts >18 years old • Each cycle is 28 days • Stem cell harvest after >4 cycles of CRd for patients <70-75 yrs • C1D1/2 – Carfilzomib dose is 20 mg/m2 • C1- 4 – Dex dose is 20 mg, C5- 8 – Dex dose is 10 mg Korde et al. JAMA Oncology 2015; 1(6): 746-53

38. Response rates in relation to cycles of KRd nCR/CR/sCR 8% 58% 83% 100% Mean M-spike (d/dL) 11/12 (92%) are MRD negative by 8-color flow cytometry of the bone marrow 9/12 (75%) are MRD negative by NGS of the bone marrow Korde et al. JAMA Oncology 2015; 1(6): 746-53

39. Curative Estrategia Smoldering Alto Riesgo (CESAR trial)(n:90) Induction6 cycles of KRd MRD ASCT(melphalan 200) MRD Consolidation (2 cycles of KRd) MRD Maintenance(Len-dex for 2yrs) MRD Primaryobjective: To evaluatetheproportion of patients in sustainedimmunophenotypic response at 5 years Hypothesis: At least 50% of patientswillachievetheobjective 20 centers

40. Conclusions New definition of MM, myeloma defining event New definition of smoldering High-risk smoldering ? New clinical trials  cure ?