ohio state's ash review 2017 - update in myeloma
TRANSCRIPT
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Update in Myeloma: ASH 2016
Don M Benson Jr, MD PhD, FACPAssociate Professor of Medicine | Head of Translational Research
Division of HematologyThe Ohio State University Comprehensive Cancer Center
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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
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Daratumumab
DemographicsPOLLUX (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
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Daratumumab
ASH 2016 Abstracts 489, 1150, 1151
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Daratumumab
ASH 2016 Abstracts 489, 1150, 1151
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Daratumumab
ASH 2016 Abstracts 489, 1150, 1151
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Daratumumab
ASH 2016 Abstracts 489, 1150, 1151
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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
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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)
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Daratumumab
Abstract 1149
“PAVO”: Phase 1b study of SQ daratumumab with rHuPH20‐ co‐formulate approved in Europe for trastuzumab and rituximab
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STaMINA trial
Abstract LBA‐1
MelphalanautoSCT
Len maintenance
VRD x 4 cycles Len
maintenance
Mel autoSCTLen
maintenancen=754:‐ SOC n = 257‐ VRD n = 254‐ tandem n= 247
High risk cyto/FISH = 24%
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STaMINA trial
Abstract LBA‐1
MelphalanautoSCT
Len maintenance
VRD x 4 cycles Len
maintenance
Mel autoSCTLen
maintenancen=754:‐ SOC n = 257‐ VRD n = 254‐ tandem n= 247
High risk cyto/FISH = 24%
Adherence: 95%
Adherence: 88%
Adherence: 68%
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STaMINA trial
Abstract LBA‐1
MelphalanautoSCT
Len maintenance
VRD x 4 cycles Len
maintenance
Mel autoSCTLen
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
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Investigational agents
• Venetoclax
• Nelfinavir
• Selinexor
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Venetoclax
Abstract 488
Patients N=66
Cytogenetics/FISH (n):‐ t(11;14)‐ Other: t(4;14), del17p, del13q
3036
Prior lines: median (range) 5 (1‐15)
Prior SCT (%) 75
Bort and len refractory (%) 61
Refractory to last line (%) 79
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Venetoclax
Abstract 488
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Venetoclax + bortezomib/dex
Abstract 975
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Nelfinavir
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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
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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
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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)
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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
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Standard risk Intermediate risk High risk
Transplant ineligibleVRD 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 maintenancex 1 year
Bortezomib maintenance x 1 year
Transplant eligibleVRD 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 maintenancex 2 years
First line
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First relapseOn 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
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Second or later relapseNo 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 lenand 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) ORSecondary 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
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Summary • Daratumumabcombinations
• SCT len
• On the radar:– Venetoclax for t(11;14)– Nelfinavir– Selinexor
• Guideline updates:• VRD induction• Class switching at relapse• Daratumumab combinations