Don M. Benson Jr., MD, PhD, FACP Associate Professor of Medicine Head of Translational Research Division of Hematology The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

1. Update in Myeloma: ASH 2016
Don M Benson Jr, MD PhD, FACP
Associate Professor of Medicine | Head of Translational Research
Division of Hematology
The Ohio State University Comprehensive Cancer Center

2. Objectives
• 1. Review new data with approved therapies
• Daratumumab
• Role of stem cell transplantation
• 2. Review data on investigational agents
• Venatoclax
• Nelfinavir
• Selinexor
• 3. Integrate new evidence to practice guidelines

3. Daratumumab
Demographics
POLLUX (n=569)
Len/dex ± dara
CASTOR (n=498)
Bort/dex ± dara
Patient information:
Median age (years) 65 64
ISS stage 3 (%) 20 22
High risk cyto/FISH (%) 20 27
Treatment history:
1 prior line (%) 52 47
> 3 prior lines (%) 6 10
‐ Prior SCT (%) 63 61
‐ Prior PI & IMID 44 50
‐ Refractory to IMID (%) n/a 33
‐ Refractory to bortezomib (%) 21 n/a
POLLUX New Eng J Med 2016; 375: 1319‐31 & CASTOR New Eng J Med 2016; 375: 754‐66

4. Daratumumab
ASH 2016 Abstracts 489, 1150, 1151

5. Daratumumab
ASH 2016 Abstracts 489, 1150, 1151

6. Daratumumab
ASH 2016 Abstracts 489, 1150, 1151

7. Daratumumab
ASH 2016 Abstracts 489, 1150, 1151

8. Daratumumab
Abstract 489
POLLUX (New Eng J Med 2016; 375: 1319‐31)
‐ len / dex vs. len / dex / daratumumab
‐ 1‐3 prior lines
lenalidomide‐naïve results (n=219 v 226)
Outcome Len/dex + dara p value
PFS (mo) 18.4 N/R < 0.0001
1‐yr PFS (%) 59 83
ORR (%) 79 96 < 0.0001
≥ VGPR (%) 47 76 < 0.0001
≥ CR (%) 21 44 < 0.0001
Prior lenalidomide results (n=45 v 46)
Outcome Len/dex + dara p value
PFS (mo) N/R N/R
1‐yr PFS (%) 63 81
ORR (%) 71 87 0.0729
≥ VGPR (%) 38 78 0.0001
≥ CR (%) 12 44 0.0011
bortezomib‐naïve results (n=45 v 44)
Outcome Len/dex + dara p value
PFS (mo) 15.8 N/R 0.017
1‐yr PFS (%) 69.2 85.4
ORR (%) 82 98 0.0158
≥ VGPR (%) 55 74 0.0544
≥ CR (%) 23 42 0.0576
Bortezomib‐refractory results (n=49 v 54)
Outcome Len/dex + dara p value
PFS (mo) 10.3 N/R 0.0117
1‐yr PFS (%) 44.4 70.8
ORR (%) 68 92 0.0024
≥ VGPR (%) 36 75 0.0001
≥ CR (%) 13 46 0.0003

9. Daratumumab
Abstract 1149
“PAVO”: Phase 1b study of SQ daratumumab with rHuPH20
‐ co‐formulate approved in Europe for trastuzumab and rituximab
• Eligibility:
– ≥ 3 prior lines
• PI & IMID
• 1200mg (n=8)
– In 60mL / 20min
• 1800mg (n=45)
– In 90mL / 30 min
TEAE 1200mg 1800mg
AE profile of DARA‐PH20 consistent with IV daratumumab
Any drug‐related (%) 63 62
Anemia (%) 13 13
Low platelets (%) 13 7
Neutropenia (%) 13 7
Hypertension (%) 25 4
Fatigue (%) 25 2
Device‐related
infection (%)
0 4
Infusion related (%) 13 24 (all Gr 1 or 2)

10. Daratumumab
Abstract 1149
“PAVO”: Phase 1b study of SQ daratumumab with rHuPH20
‐ co‐formulate approved in Europe for trastuzumab and rituximab

11. STaMINA trial
Abstract LBA‐1
Melphalan
autoSCT
Len
maintenance
VRD x 4 cycles
Len
maintenance
Mel autoSCT
Len
maintenancen=754:
‐ SOC  n = 257
‐ VRD  n = 254
‐ tandem  n= 247
High risk cyto/FISH = 24%

12. STaMINA trial
Abstract LBA‐1
Melphalan
autoSCT
Len
maintenance
VRD x 4 cycles
Len
maintenance
Mel autoSCT
Len
maintenancen=754:
‐ SOC  n = 257
‐ VRD  n = 254
‐ tandem  n= 247
High risk cyto/FISH = 24%
Adherence: 95%
Adherence: 88%
Adherence: 68%

13. STaMINA trial
Abstract LBA‐1
Melphalan
autoSCT
Len
maintenance
VRD x 4 cycles
Len
maintenance
Mel autoSCT
Len
maintenancen=754:
‐ SOC  n = 257
‐ VRD  n = 254
‐ tandem  n= 247
High risk cyto/FISH = 24%
PFS (%) HR PFS OS SPM
52 40 83 4
PFS (%) HR PFS OS SPM
56 38 82 5.9
All p‐values = n/s
PFS (%) HR PFS OS SPM
57 48 86 6
Median follow up 38 months

14. Investigational agents
• Venetoclax
• Nelfinavir
• Selinexor

15. Venetoclax
Abstract 488
Patients N=66
Cytogenetics/FISH (n):
‐ t(11;14)
‐ Other: t(4;14), del17p, del13q
30
36
Prior lines: median (range) 5 (1‐15)
Prior SCT (%) 75
Bort and len refractory (%) 61
Refractory to last line (%) 79

16. Venetoclax
Abstract 488

17. Venetoclax + bortezomib/dex
Abstract 975

18. Nelfinavir

19. Nelfinavir – SAKK 39/13 trial
Patient population (n=34)
Age, med 67 (42‐82)
Prior therapy, med 5 (2‐10)
Prior SCT (%) 76
Poor risk cyto (%) 38
Bort refractory (%) 100
Len refractory (%) 79
Pom refractory (%) 44
Abstract 487
Response rates: (%)
Overall RR (≥ PR) 65
‐ high risk FISH 77
‐ bort + len refractory 70
‐ bort + len + pom ref 60
A phase II study of Bort/Dex +
Nelfinavir in Bort‐refractory myeloma

20. Selinexor
• “STORM” trial: phase II of CRM1/XPO1 SINE
– n=79 patients enrolled:
• Quad‐refractory (len, pom, bort, carfil) n=48
• Penta‐refractory (quad + anti‐CD38) n=31
– Median prior lines of therapy = 7
– Baseline ≥ grade 3 anemia 13%, thrombocytopenia 8%
– Common TRAE’s: cytopenias (21‐58%), GI (3‐5%), fatigue
Abstract 491

21. Selinexor
Abstract 491
Outcomes
• Median OS = 9.3 months
– Responders = N/R (> 11 months)
– Non responders = 5.7 months
• DOR 5 months
• High risk FISH = 33% ORR
– Responses observed despite:
• Del17p, t(14;16), t (4;14)

22. Standard risk Intermediate risk High risk
Trisomies t(4;14) del17p
t(11;14) 1q gain t(14;16)
t(6;14) t(14;20)
All others GEP signature
Updated practice guidelines

23. Standard risk Intermediate risk High risk
Transplant ineligible
VRD x ~ 12 months
(len/dex if ≥ 75 / frail)
VRD x ~ 12 months VRD x ~ 12 months
Len/dex x 1 year or to
progression
Bortezomib maintenance
x 1 year
Bortezomib maintenance
x 1 year
Transplant eligible
VRD x 4 cycles VRD x 4 cycles KRD x 4 cycles
SCT Collect cells SCT SCT (tandem?)
Len x at
least 2
years
Len/dex to
progression
Bortezomib maintenance
x 2 years
Bortezomib or
Carfilzomib maintenance
x 2 years
First line

24. First relapse
On maintenance Off therapy*
Fit patient* Indolent
relapse* or frail
patient
Fit patient* Indolent
relapse* or frail
patient
Len:
‐ KPD
‐ Dara/bort/dex
Bort:
‐ Dara/len/dex
Len:
‐Dara/bort/dex
‐Ixa/cytox/dex
Bort:
‐Dara/len/dex
‐Ixa/len/dex
‐ KRD
‐ Dara/len/dex
‐Ixa/len/dex
‐Elo/len/dex
* SCT if not already performed; 2nd SCT if > 18 months PFS or > 36 months PFS

25. Second or later relapse
No plasma cell leukemia / extramedullary disease
Single refractory* Dual refractory* Triple refractory* Triple refractory*
Refractory to IMID:
‐ Dara/bort/dex
Refractory to PI:
‐ Dara/len/dex**
Refractory to len
and bort/ixa:
‐ KPD / KRD
‐ Pom‐based
regimen + dara**
Refractory to len,
bort/ixa, carfil:
‐Pom‐based +
dara**
Refractory to len,
pom, bort/ixa:
‐dara‐based**
‐Alkylator‐based
‐Bort/dex/pano
* SCT if not already performed; 2nd SCT if > 18 months PFS or > 36 months PFS
** if daratumumab‐refractory, use elotuzumab
Quadruple refractory (len, pom, bort/ixa, carfil) OR
Secondary plasma cell leukemia / extramedullary disease
VDT‐PACE x 2 cycles (or CVAD if older / poor PS)
‐‐‐‐
SCT (if candidate), other options include: dara‐based, pano‐
containing, alkylator combination, anthracycline combination

26. Summary
• Daratumumab
combinations
• SCT  len
• On the radar:
– Venetoclax for t(11;14)
– Nelfinavir
– Selinexor
• Guideline updates:
• VRD induction
• Class switching at relapse
• Daratumumab combinations