1. Magic Iceland

2. Recent advances And Future hopes
Treatment of Myeloma
Recent advances 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
CORE
9/11/2018 7:29 PM
Multiple Myeloma Survival Improving With New Drugs AA
Adapted from Kumar et al Leukemia 2014
DRAFT

5. 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

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

9. 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 %

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

12. 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

13. 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

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
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

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

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
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.

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: 23 23

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

25. 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 =
VMP: 24.0 months
MP: 16.6 months, P < 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):

26. 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 mg days 1-21/28
LoDEX mg days 1, 8, 15, 22/28
MEL + PRED + THAL 12 Cycles (72 weeks)
MELPHALAN mg/kg days 1-4/42
PREDNISONE mg/kg days 1-4/42
THALIDOMIDE 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 mg days 1-21/28
LoDEX 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:

27. 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

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

29. 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

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
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

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. 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, ; 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

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%
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

41. 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.

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
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

43. Phase 3 Rd-based Continuous Studies for Elderly Patients
NCT
NCT
NCT
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 & 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 & 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 & d cycles/18 mos
Primary endpoint for all studies is PFS
1. NCT NCT NCT

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. Active Treatment + PFS Follow-up Phase PD or Unacceptable Toxicity
A french study for frail elderly NDMM patients; IFM 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)

47. 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