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Magic Iceland

Explore the latest treatments and advancements in the management of myeloma, including the use of targeted therapy and novel agents. Learn about the IFM experience and the potential benefits of autologous transplantation, consolidation therapy, and maintenance therapy. Discover the impact of minimal residual disease negativity and upfront ASCT on patient outcomes.

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Magic Iceland

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  1. Magic Iceland

  2. Treatment of Myeloma Recentadvances And Future hopes The IFM experience Jean Luc Harousseau

  3. Venetoclax in MM with t(11;14)The first targeted therapy in MM ?

  4. Multiple Myeloma Survival Improving With New Drugs AA 1960-65 1965-70 1970-75 1975-80 1980-85 1985-90 1990-95 1995-00 2000-05 2005-10 Adapted from Kumar et al Leukemia 2014

  5. Transplant-eligible patients • Autologous transplantation isactually - High-dose therapy (Melphalan) - Supported by patients hematopoietic stem cells -Collected in the peripheralblood - Cryopreserved • Eligible patients - up to 65 years of age - fit and withoutseverecomorbidities

  6. First-generation New Agents • Thalidomide (immunomodulator) • Lenalidomide/Revlimid (immunomodulator) • Bortezomib/Velcade (Proteasome-inhibitor)

  7. In the era of « novel » agents HDT/ASCT Is no longer just HDT supported by ASCT But is a part of a complex multistep prodedure ASCT Consolidation Induction therapy Maintenance Melphalan 200 mg/m2 2-3 CYCLES « novel» agents Or Second ASCT Lenalidomide Bortezomib 3-4 CYCLES « novel » agents

  8. Induction therapy with novel agents • Triple Combination > Double Combination - VTD > TD Cavo M Lancet 2010;376:2075 Rosinol L Blood 2012;120:1589 - vTD > VD Moreau P Blood 2011;118:5752 • Triplets shouldcontain1 IMId and 1 PI - VTD >VCD Moreau P (Blood 2016;127:2569-2574) • VTD (Velcade/Thalidomide/Dexamethasone) isthe standard induction regimen • ShouldRevlimid replace Thalidomide (RVD) ?

  9. CONSOLIDATION THERAPY • 2 or 3 courses (oftenidentical to induction therapy) ex VTD induction and consolidation (Cavo M Lancet 1010;376:2075) • Improves the response rate (Cavo M Blood 2012;12:9) and upgrades the level of response: undetectabledisease by sensitive techniques (LadettoM JCO 2010;18:2077) • IFM experience(Roussel M JCO 2014;32:2712)

  10. Maintenance therapy with low-dose lenalidomide until progression dramatically improves PFS Attal M (IFM) NEJM 2012;366:1782 Mc Carthy P (CALGB) NEJM 2014,371:1770 Palumbo A NEJM 2014;371:895

  11. Lenalidomide maintenance OS • Meta-analysis of the 3 trials (1208 pts, 79.5 mo median f-up) • The benefit of a longer duration of first response translates into a longer OS onlyafter 5 years Mc Carthy P (JCO 2017 online)

  12. LENALIDOMIDE MAINTENANCE REMAINING QUESTIONS • Lenalidomide maintenance after ASCT isnowapproved by FDA and EMA • Howeverlessconvincingresults in high-risk MM (ISS3, poor-riskcytogenetics)  Bortezomib ? • Toxicity of long-termtreatment - 29% of AE treatment discontinuation - 4.3% SPM vs 1% • Cost (unaffordable in some countries) • Optimal duration stillunknown

  13. During the sameperiod non-intensive treatmentalsoimprovedwithnovel agentsSWOG trial (525 pts)eight 21-d cycles of RVd vs six 28-d cycles of Rd Durie B et al Lancet 2017;389:519

  14. IFM/DFCI 2009 Study Early vs Late ASCT in newly diagnosed MM pts up to 65 years Randomize RVDx3 RVDx3 CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg Melphalan 200mg/m2* + ASCT RVD x 5 RVD x 2 Revlimid Revlimid SCT at relapse MEL 200 mg/m2 if <65 yrs , >65 yrs 140mg/m2

  15. IFM 2009 (9/2015) Median F-up 43 months PFS Median 36 m vs 50 m 4-yr PFS 35%vs 50 % HR 0.65 OS 4-yr SV >80 % in both arms

  16. IFM 2009 : PFS

  17. IFM 2009 The impact of Minimal Residual Disease Negativity

  18. IFM 2009 Impact of MRD (NGS)PFS according to treatment arm

  19. Prognostic Impact of PET- CT normalization before maintenance in the IFM/DFCI trial (134 pts) PFS p=0.011 OS p=0.033 Moreau P et al JCO 2017;35:2911

  20. Summary of IFM 2009 results Compared to the best non-intensive treatment to-date ( 65 % <0 MRD, 36 months PFS) UPFRONT ASCT Longer PFS in all prognostic subgroups More patients with negative MRD BUT No difference in OS…. Due to excellent results of RVD and to more possibilities at time of relapse including ASCT in 2/3 of cases To show an OS benefit more F-up is needed

  21. Intensive versus non-intensive upfront treatment Four randomized studies Palumbo A et al NEJM 2014;371:895 Gay P Lancet Oncol 2015;16:1617 Attal M et al NEJM 2017;376:1311 Cavo P et al ASH 2016 Patients could receive HDT/ASCT at relapse in the non-intensive arm All 4 studies show a significant benefit in terms of PFS in the intensive arm Autotransplantation remains he standard of care But non intensive treatment with RVD is a valuable alternative

  22. FOLLOW-UP OF IFM S9321 TT PROTOCOLS Overall Survival IFM 2009 IFM 2005 TT3: all risk, age <75 TT2: all risk, age <75 IFM99-02: low risk, age <65 TT1: all risk, age <75 IFM90: all risk, age <65 IFM94: all risk, age <65 IFM99-04: high risk, age <65 S9321: all risk, age <70 IFM 99 IFM 94 IFM 90 Barlogie, Attal et al.

  23. No improvement in the 10-Yea Survival in patients over 70 years of age before introduction of new agents Brenner et al; Blood 2008; 111:2521-26

  24. MPT Becomes a Standard of Care Facon T, et al. Lancet. 2007;370:1209-18. Fayers PM, et al. Blood. 2011;118: 1239-47.

  25. 100 100 0 0 Median follow-up 60 months Median OS: VMP: 56m MP: 43m,P = 0.0008 VMP MP 6 3 12 18 6 24 9 30 36 12 42 15 48 18 54 60 21 66 24 72 27 78 VMP becomes a standard of care VISTA Trial: Final analysis 80 80 60 60 RR (CR) (%): 71(30) vs. 35(4) 40 40 TTP OS 20 20 0 0 Patients without event (%) Patients without event (%) VMP: 24.0 months MP: 16.6 months, P < 0.000001 Time (months) Time (months) San Miguel et al. JCO 2013; 31(4):448-55.

  26. Rd becomes a standard of careIFM 2007-01-MM-020- FIRST: Study Design Screening Active Tx + PFS Follow-Up Phase LT Follow-Up PD, OS, and Subsequent anti-MM Tx PD or Unacceptable Toxicity RANDOMIZATION 1:1:1 (N = 1623) Arm A Rd Continuous (n = 535) LEN + LoDEX: Continuously LENALIDOMIDE 25 mg days 1-21/28 LoDEX 40 mg days 1, 8, 15,22/28 Arm B Rd18 (n = 541) LEN + LoDEX: 18 Cycles (72 weeks) LENALIDOMIDE 25 mg days 1-21/28 LoDEX 40 mg days 1, 8, 15, 22/28 MEL + PRED + THAL 12 Cycles (72 weeks) MELPHALAN 0.25 mg/kg days 1-4/42 PREDNISONE 2 mg/kg days 1-4/42 THALIDOMIDE 200 mg days 1-42/42 Arm C MPT (n = 547) Pts aged > 75 yrs: LoDEX 20 mg days 1, 8, 15, 22/28; THAL 100 mg days 1-42/42; MEL0.2 mg/kg days 1-4 FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; ISS, International Staging System; LoDex, low-dose dexamethasone; LT, long-term; MM, multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; pts, patients; Tx, treatment. Benboubker L, et al. N Engl J Med. 2014;371:906-17.

  27. FIRST trial (1623 pts)MPT 12 cycles vs Rd 12 cyclesvs Rd continuousRd is better than MPT but optimal duration unknown PFS OS T Facon ASH 2016

  28. Other current approaches • Combine IMId (thalidomide or lenalidomide)and PI (bortezomib) • Induction plus Maintenance with Bortezomib or Lenalidomide Ex : MRC XI trial

  29. MRC Myeloma XI StudyTransplant non-eligible pathwaySignificant improvement in PFS from 11 to 24 months, HR=0.42 100 80 60 Patients alive and progression-free (%) 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 Time since randomisation (months) No. of patients at risk: Lenalidomide Observation 406 317 374 258 319 198 281 152 227 116 190 95 154 72 133 59 102 46 84 27 74 22 62 16 51 12 42 9 29 8 24 4 13 4 10 2 7 1 6 1 2 1 0 0

  30. Conclusions Introduction of « novel »  agents was actually the first improvement of MM treatment in the elderly Use of one or two «  novel » agents increased response rate, PFS and OS Prolonged treatment is important but optimal duration is unknown Assessment of fitness/frailty is necessary for optimal treatment selection

  31. Myeloma Drug Development DurvAtezolizumab* alumab* • Nivolumab* • Pembrolizumab* Melflufen* Selinexor* Venetoclax* Nelfinavir*

  32. Continuing evolution of myeloma treatment: 1st Generation novel agents 2nd Generation novel therapies/Immunotherapy Lenalidomide Carfilzomib • Vaccines* Ixazomib Thalidomide • Daratumumab DurvAtezolizumab* alumab* Marizomib* Pomalidomide Bortezomib + Doxil Bortezomib • Elotuzumab Oprozomib* • Nivolumab* • Pembrolizumab* 3rd Generation IMiDs* • Panobinostat • AC-241/1215* Melflufen* Selinexor* Venetoclax* Nelfinavir* • CAR-T* Isatuximab* • 2017+ • 2003 • 2006 • 2007 • 2012 • 2013 • 2015 • IMiD • HDAC inhibitor • Monoclonal antibody Proteasome inhibitor Targeted Therapy • Adoptive T cell therapy • Checkpoint inhibitors • Vaccines Adapted from Richardson PG. et al ASH 2015, MMRF 2016

  33. Recently approved new agents New Immunomodulator Pomalidomide (Pomalyst/Imnovid) Used in relapse (including relapse post Lenalidomide) Double or Triple combinations Toxicity similar to Lenalidomide

  34. Recently approved new agents New Immunomodulator New Proteasome Inhibitors ► Carfilzomib ( Kyprolis) - IV infusion on 2 consecutive days - less neurotoxicity but more cardio toxicity than Bortezomib - at higher doses carfilzomibn pkus dex superior to bortezomib plus dex - in relapse (double or triple combinations) - studies in frontline treatment

  35. Recently approved new agents New Immunomodulator New Proteasome Inhibitors ► Carfilzomib ( Kyprolis) ► Ixazomib (Ninlaro) - oral (once weekly) - well tolerated - convenient for elderly patients and maintenance? - optimal dose ?

  36. Recently approved new agents New Immunomodulator New Proteasome Inhibitors Antibodies ► Elotuzumab ► anti CD 38 (Daratumumab) - IV infusion (SC currently evaluated) - well tolerated except infusion-related events with the first infusion) - the most effective new agent

  37. DaratumumabRevlimid Dexamethasone vs RevlimidDexamethasone in Relapsed MM (Pollux trial) : Updated Efficacy 100 Median: not reached • Median (range) follow-up: 17.3 (0-24.5) months 80 18-month PFSa P <0.0001 60 ORR = 93% % surviving without progression 76% ORR, % ORR = 76% DRd 40 ≥CR: 46%b ≥CR: 20% 49% 20 ≥VGPR: 78%b ≥VGPR: 45% Rd Median: 17.5 months 0 0 3 6 9 12 15 18 21 24 27 Months No. at risk 159 227 132 194 48 82 5 15 0 1 0 0 206 249 181 237 Rd DRd 249 266 283 286 HR: 0.37 (95% CI, 0.28-0.50; P <0.0001) 32% <0 MRD at 10-4 threshold

  38. WHAT IS THE NEXT STEP?IFM 2018 Objectives Increase the rate of MRD negativity – by using second-generation new agents

  39. IFM Pilot Study with KRd Roussel M et al ASH 2016

  40. RESPONSE RATES at the completion of Consolidation 4 patients were not evaluable due to toxicities MRD CMF 10-4/10-5 MRD NGS clonoSEQ Adaptive 10-6

  41. CASSIOPEA-MMY3006 Study design Induction Consolidation Maintenance ASCT VTD + DARAx 2 cycles VTD + DARAx 4 cycles RANDOMIZ ATION RANDOMIZ ATION DARA until progression dara S C R MEL E 200/ E ASCT NIN G VTDx 4 cycles VTDx 2 cycles Observation DARA, daratumumab.

  42. CLARION study KMP vs VMP Progression-Free Survival and Response rates • KMP(n=478) • 207 (43.3)22.3 • VMP(n=477) • 214 (44.9)22.1 • Disease progression or death – n (%)Median PFS – monthsHR for KMP vs VMP (95% CI) 1.0 0.8 0.6 0.4 0.2 0 • 0.91 (0.75–1.10)1-sided P=0.16 Proportion Event-Free ORR; 84.3% KMP vs. 78.8% VMP CR; 25.9% KMP vs. 23.1% VMP • KMPVMP 0 6 12 18 24 30 36 Months Number at risk: KMP VMP 478 477 384 367 327 309 217 202 85 77 15 9 0 0 Facon et al, IMW meeting 2017, oral presentation • Median follow-up time: 22.2 months for KMP and 21.6 months for VMP • The absence of PFS difference was consistent across subgroups

  43. Phase 3 Rd-based Continuous Studies for Elderly Patients • Primary endpoint for all studies is PFS NCT01335399 NCT01850524 NCT02252172 Rd R: 25 mg PO ; D1–21 DEX: 40 mg PO ; D1, 8, 15 & 2228-d cycles until PD ELO-Rd ELO: 10 mg/kg; D1, 8, 15 & 22 (cycles 1–2); D1 & 15 (cycles 3–18); 20 mg/kg on D1 (cycles ≥ 19) R: 25 mg, D1–21 DEX: 40 mg D1, 8, 15 & 22 (cycles 1–2); D1 & 15 (cycles 3–18); D1 (cycles ≥ 19) 28-d cycles, until PD Rd R: 25 mg PO ; D1–21 DEX: 40 mg PO ; D1, 8, 15 & 2228-d cycles/18 mos Ixazomib-Rd Ixazomib: 4 mg R: 25 mg DEX: 40 mg; D1, 8, 15 & 22 28-d cycles/18 mos Rd R: 25 mg PO ; D1–21 DEX: 40 mg PO ; D1, 8, 15 & 2228-d cycles until PD DARA-Rd DARA: 16 mg/kg q1wk for 8 wks; q2wk for 16 wks; q4wk thereafter R: 25 mg PO d; D1–21 DEX: 40 mg PO d; D1, 8, 15 & 22 Elotuzumab Ixazomib Daratumumab DEX Discontinued DEX Discontinued Ixazomib+ R Ixazomib: 3 mgR: 10 mg Until PD Placebo + R R10 mg Until PD 1. NCT01335399. 2. NCT01850524. 3. NCT02252172.

  44. WHAT IS THE NEXT STEP?IFM 2018 Objectives Increase the rate of MRD negativity – by using new agents – by prolonging the duration of induction and consolidation Adapt treatment to results of MRD assessment Address again the question of the role of ASCT in standard risk patients with <0 MRD after induction Tailor treatment to initial prognostic factors (double ASCT ?)

  45. Outcome by Frailty level in the First trial PFS OS

  46. A french study for frail elderly NDMM patients; IFM 2018-01A dexamethasone sparing study LT Follow-Up Active Treatment + PFS Follow-up Phase LEN + Dara SC continuously: LENALIDOMIDE 25mg D1-21/28 DARATUMUMAB SC 1800 mgSC Q1Wk for 8 weeks 1800 mg SC Q2Wk for 16 weeks 1800 mg SC Q4Wk thereafter PD or Unacceptable Toxicity PD, OS and Subsequent anti-MM Tx RANDOMIZATION 1:2 2 Arm A R-DaraSC LEN + Lo-DEX continously: LENALIDOMIDE 25mg D1-21/28 Lo-DEXAMETHASONE 20mg D1,8,15 & 22/28 Arm B Rd 1 Randomization will be stratified by International Staging System (I vs II vs III) and age (<80 vs ≥80 s In Arm A Cycle 1 and 2 then Methylprednisolone (with SC Dara)

  47. CONCLUSION The prognosis of MM patients has dramatically improved over the past 15 years with the introduction of IMIds and PI More CR, longer remissions, more solutions at relapse LONGER SURVIVALS MRD negativity and PETCT negativity can be obtained and are associated with longer remissions (possibly cures ?) NEW OBJECTIVE OF TREATMENT The addition of newer agents (anti-CD38 antibodies) Daratumumab is likely to increase the MRD <0 rate Treatments may become tailored according to - initial prognostic factors (ISS, Cytogenetics , frailty) - - response to treatment

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