Magic Iceland

Recent advances And Future hopes Treatment of Myeloma Recent advances And Future hopes The IFM experience Jean Luc Harousseau

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

Multiple Myeloma Survival Improving With New Drugs CORE 9/11/2018 7:29 PM 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 DRAFT

Transplant-eligible patients Autologous transplantation is actually - High-dose therapy (Melphalan) - Supported by patients hematopoietic stem cells -Collected in the peripheral blood - Cryopreserved Eligible patients - up to 65 years of age - fit and without severe comorbidities

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

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 Induction therapy ASCT Consolidation Maintenance Melphalan 200 mg/m2 2-3 CYCLES « novel» agents Or Second ASCT Lenalidomide Bortezomib 3-4 CYCLES « novel » agents

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 should contain 1 IMId and 1 PI - VTD >VCD Moreau P (Blood 2016;127:2569-2574) VTD (Velcade/Thalidomide/Dexamethasone) is the standard induction regimen Should Revlimid replace Thalidomide (RVD) ?

VRD CONSOLIDATION (N=30) CONSOLIDATION THERAPY 2 or 3 courses (often identical 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: undetectable disease by sensitive techniques (Ladetto M JCO 2010;18:2077) IFM experience (Roussel M JCO 2014;32:2712) AFTER VRD Induction (N=31) ASCT (N=30) VRD CONSOLIDATION (N=30) 23 % 47 % 50 % 58 % 70 % 87 % 94 % 93 % 97 % MRD < O (FC) 26 patients 16 % 54 %

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

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 only after 5 years Mc Carthy P (JCO 2017 online)

LENALIDOMIDE MAINTENANCE REMAINING QUESTIONS Lenalidomide maintenance after ASCT is now approved by FDA and EMA However less convincing results in high-risk MM (ISS3, poor-risk cytogenetics)  Bortezomib ? Toxicity of long-term treatment - 29% of AE  treatment discontinuation - 4.3% SPM vs 1% Cost (unaffordable in some countries) Optimal duration still unknown

During the same period non-intensive treatment also improved with novel agents SWOG trial (525 pts) eight 21-d cycles of RVd vs six 28-d cycles of Rd Durie B et al Lancet 2017;389:519

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 AB added slide to backup section outlining each regimen in case questions arise RVD x 2 Revlimid Revlimid SCT at relapse MEL 200 mg/m2 if <65 yrs , >65 yrs 140mg/m2

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 This result is illustrated on this slide: Transplantation: the red curve RVD: the blue curve.

IFM 2009 : PFS

IFM 2009 The impact of Minimal Residual Disease Negativity

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

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

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

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

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 So using these improved strategies we have been able to decrease the residual disease over time and this decrease has been associated with an improved overall survival as illustrated on this slide which is a metanalysis of the IFM and little rock group trials. … IFM 90 Barlogie, Attal et al.

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 23 23

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

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

Rd becomes a standard of care IFM 2007-01-MM-020- FIRST: Study Design RANDOMIZATION 1:1:1 (N = 1623) Arm C MPT (n = 547) 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 Subsequent anti-MM Tx PD, OS, and PD or Unacceptable Toxicity Active Tx + PFS Follow-Up Phase Screening LT Follow-Up Pts aged > 75 yrs: LoDEX 20 mg days 1, 8, 15, 22/28; THAL 100 mg days 1-42/42; MEL 0.2 mg/kg days 1-4 LEN + LoDEX: Continuously LENALIDOMIDE 25 mg days 1-21/28 LoDEX 40 mg days 1, 8, 15,22/28 Arm A Rd Continuous (n = 535) The final PFS data has been presented previously and is published in the NEJM (2014). 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.

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

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

Median PFS, months [95% CI] MRC Myeloma XI Study Transplant non-eligible pathway Significant improvement in PFS from 11 to 24 months, HR=0.42 Time since randomisation (months) 100 Patients alive and progression-free (%) 80 60 40 20 18 33 51 63 3 6 9 12 15 21 24 27 30 36 39 42 45 48 54 57 Median PFS, months [95% CI] Lenalidomide (n=406) 24 [21, 30] Observation (n=317) 11 [9, 13] 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 10 2 7 1 6

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

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

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

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

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

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 ?

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

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

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

IFM Pilot Study with KRd Roussel M et al ASH 2016

RESPONSE RATES at the completion of Consolidation % sCR 26 57 MRD - CMF 32 70 MRD - NGS 23/34 68 At least CR 28 61 At least VGPR 39 85 ORR 41 89 PD 1 2 N=46 n % sCR 26 57 MRD - CMF 32 70 MRD - NGS 23/34 68 N=46 n % sCR 26 57 4 patients were not evaluable due to toxicities MRD CMF 10-4/10-5 MRD NGS clonoSEQ Adaptive 10-6

CASSIOPEA-MMY3006 Study design Induction ASCT Consolidation Maintenance VTD + DARA x 4 cycles VTD + DARA x 2 cycles R A N D O M I Z A T I O N R A N D O M I Z A T I O N DARA until progression dara S C R E N I N G MEL 200/ ASCT VTD x 4 cycles VTD x 2 cycles Observation DARA, daratumumab.

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 1.0 0.8 0.6 0.4 0.2 Disease progression or death – n (%) Median PFS – months HR for KMP vs VMP (95% CI) 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 KMP VMP 6 12 18 24 30 36 Months Number at risk: KMP VMP 478 477 384 367 327 309 217 202 85 77 15 9 Median follow-up time: 22.2 months for KMP and 21.6 months for VMP The absence of PFS difference was consistent across subgroups Facon et al, IMW meeting 2017, oral presentation

Phase 3 Rd-based Continuous Studies for Elderly Patients NCT01335399 NCT01850524 NCT02252172 Elotuzumab Ixazomib Daratumumab Placebo + R R 10 mg Until PD Ixazomib+ R Ixazomib: 3 mg R: 10 mg DEX Discontinued 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 & 22 28-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 DEX: 40 mg PO ; D1, 8, 15 & 22 28-d cycles until PD Ixazomib-Rd Ixazomib: 4 mg R: 25 mg DEX: 40 mg; D1, 8, 15 & 22 28-d cycles/18 mos DEX: 40 mg PO ; D1, 8, 15 & 22 28-d cycles/18 mos Primary endpoint for all studies is PFS 1. NCT01335399. 2. NCT01850524. 3. NCT02252172.

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 ?)

Outcome by Frailty level in the First trial PFS OS

Active Treatment + PFS Follow-up Phase PD or Unacceptable Toxicity A french study for frail elderly NDMM patients; IFM 2018-01 A dexamethasone sparing study LT Follow-Up Active Treatment + PFS Follow-up Phase RANDOMIZATION 1:2 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 Subsequent anti-MM Tx PD, OS and 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)

CONCLUSION LONGER SURVIVALS NEW OBJECTIVE OF TREATMENT 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