1
Multiple Myeloma Patient Management: New Agents, New Challenges
8:15 AM – 8:25 AM Community Case 1 Robert M. Rifkin, MD
8:25 AM – 8:40 AM Advances in the Diagnostic Workup: Imaging and GenomicsA. Keith Stewart, MBChB
8:40 AM – 8:55 AM Making Sense of Frontline OptionsThierry Facon, MD
8:55 AM – 9:05 AM Community Case 2Robert M. Rifkin, MD
9:05 AM – 9:20 AM Strategies to Prolong ResponseAmrita Y. Krishnan, MD
9:20 AM – 9:35 AM Panel Discussion9:35 AM – 9:45 AM Community Case 3
Robert M. Rifkin, MD9:45 AM – 10:00 AM New Agents, Classes in the Relapsed Setting
Faith E. Davies MD10:00 AM – 10:15 AM The Way Forward: Immunotherapy
Paul G. Richardson, MD10:15 AM – 10:30 AM Panel Discussion10:30 AM – 11:00 AM Question and Answer Session
2
Patient Case 1
Robert M. Rifkin, MDAssociate Chair – US Oncology Research
Disease Lead – Multiple MyelomaAttending Physician
Rocky Mountain Cancer CentersDenver, Colorado
Case Study 1• 75-year-old man referred for workup of back pain
that radiated to ribs and chest. • CT pulmonary Angiogram was negative for
pulmonary embolus (creatinine 1.5).• This showed multifocal lytic bone disease. Felt
well except for pain in his back.
3
Case Study 175-year-old man referred for workup of back pain that radiated to ribs and
chest.
• Hypertension• T2DM• Coronary artery disease with 2 stents
Past medical history
• Left rotator cuff repair 7 years ago
Past surgical history
• Brother and five sisters—all healthy
• Four children
Familyhistory
• Married, bilingual instructor for OSHA
• Nonsmoker, rare social alcohol
• No substance use
Socialhistory
• Normal• ROS: negative except for back pain
Physicalexam
Case Study 1: Labs ActualValue
Normal Range
CBC withdifferential
WBC (103/mL) 5.4 (4–11)
Hemoglobin (g/dL) 12.0 (13–16)
Hematocrit (%) 38 (34–45)
Platelets (103/mL) 210 (150–400)
Neutrophils (103/mL) 4.3 (1.9–7.5)
CMP
BUN (mg/dL) 34 (7–20)
Creatinine (mg/dL) 1.5 (0.7–1.2)
Calcium (mg/dL) 9.4 (8.4–10.2)
Total protein (g/dL) 8.7 (6.3–8.2)
Albumin (g/dL) 3.7 (3.5–5.0)
β2M 4.5
SPEP + serum immuno-fixation
IF-IgG
M protein spike (g/dL) 1.7
ActualValue
Normal Range
QuantitativeIgs
IgG (mg/dL) 2,425 (H) (700–1,600)
IgA (mg/dL) 20 (L) (70–400)
IgM (mg/dL) 3 (L) (40–230)
FLC
Kappa quant Free Lite Chain (mg/L)
112 (H) (3.30–19.40)
Lambda quant FLC (mg/L) 1.8 (L) (5.71–26.30)
Kappa/lambda quant FLC ratio
62.2 (H) (0.26–1.65)
4
Case Study 1: Imaging and BM Biopsy
Skeletal survey• 1.6 cm lytic lesion
in the parietal bone; severe loss of bone mineralization—osteoporosis
PET scan• Expansile lytic
lesion in right acromion. Multiple areas of uptake in bilateral ribs, and increased uptake in T5
Boneimaging
• Multifocal lesions in spine and ribs
MRI
• 70% cellular with 70%–80% plasma cells
• Aspirate 66% plasma cells
BMbiopsy
• 25.6% events positive for CD38, CD56, CD138, and kappa light chain
Flow cytometry
Cytogenetics• 46, XYFISH (CD138 selected plasma cells)• 74% with gain of
1q21• 5.4% low-level gain
of 11q23• 91% with loss of
13q14• 12.0 % with low-
level loss of TP53• 92.5% positive for
IgH rearrangement variant
Cytogenetics and FISH
Advances in the Diagnostic Workup: Imaging and Genomics
A. Keith Stewart, MBChB, MRCP, FRCPC, MBACarlson and Nelson Endowed Director
Center for Individualized MedicineVasek and Anna Maria Polak Professor of Cancer ResearchConsultant, Division of Hematology/Oncology, Mayo Clinic
Rochester, Minnesota and Scottsdale, Arizona
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida
5
Improving Survival in MM
0.0
1.0
0.8
0.6
0.4
0.2
Pro
po
rtio
n S
urv
ivin
g
0.9
0.7
0.5
0.3
0.1
0 4Follow Up From Diagnosis (Years)
2 6 8 10 12 14 1816 20
25% of patients live less than 3 years
1960–19651965–19701970–19751975–19801980–19851985–19901990–19951995–20002000–20052005–2010
Adapted from Kumar SK et al. Leukemia. 2014;28:1122.
Prognostic SystemsCombining Genetics and ISS Model
+
Fonseca R et al. Leukemia. 2009;23:2210.Greipp PR et al. J Clin Oncol. 2005;23:3412.
Risk Criteria Median OS
Standard Lack of del(17p), t(4;14), t(14;16) 50.5 mo
HighAt least one of
del(17p), t(4;14) or t(14;16)
24.5 mo(P<0.001)
Table 2, page 3415:
Greipp PR et al.J Clin Oncol. 2005;23:3412.
6
Revised International Staging System(R-ISS) for MM
• R-ISS I (n=871)– Including ISS stage I (serum β2M level <3.5
mg/L and serum albumin level ≥3.5 g/dL)– No high-risk CA [del(17p) and/or t(4;14)
and/or t(14;16)]– Normal LDH level (less than the upper limit of
normal range)
• R-ISS III (n=295)– Including ISS stage III (serum β2M level >5.5
mg/L)– High-risk CA or high LDH level
• R-ISS II (n=1,894)– Including all the other possible combinations
5-Year OS* (%)
5-Year PFS* (%)
R-ISS I 82 55
R-ISS II 62 36
R-ISS III 40 24*At a median follow-up of 46 months
Palumbo A et al. J Clin Oncol. 2015;33:2863.
mSMART 2.0 Variable Outcomes in MM
High20%
Intermediate20%
Standard60%
• FISH‒ del 17p‒ t(14;16)‒ t(14;20)
• GEP‒ High-risk signature
• FISH t(4;14)• Amplification
chromosome 1q
• Others‒ Hyperdiploid‒ t(11;14)‒ t(6;14)
3–4 years 5–6 years 8–10 years
Mikhael JR et al. Mayo Clin Proc. 2013;88:360.
7
t(4;14)1
• Translocation upregulates MMSET + FGFR3• Found in 15% of patients• Associated with IgA myeloma• Immature morphology • Often associated with del17• Tendency for less lytic bone disease, younger age
t(11:14)2
• Translocation upregulates cyclinD1• Found in 20% of patients• Associated with IgD, IgM, and nonsecretory MM• Lymphoplasmacytoid morphology• Often associated with B lineage–associated Ag• Enriched for amyloid/plasma cell leukemia
1. Jaksic W et al. J Clin Oncol. 2005;23:7069.2. An G et al. Leuk Res. 2013;37:1251.
Cytogenetics: Biologically Defined Unique Subsets
Figure 2, page 2033
Garand R et al. Leukemia. 2003;17:2032.
Risk Stratification in MyelomaHow do we customize treatment?
• t(4;14) MM– Inferior outcomes with traditional ASCT– Results better with integration of novel agents, particularly BTZ
(consolidation or maintenance) and use of tandem transplant• Del17p (p53 deletion) MM
– Improved outcome for low-risk del17p with aggressive multi-combination and prolonged therapy
– New treatment approaches required (eg, immune-based approaches, use of epigenetic modulators)
• Hyperdiploid– Myc dependant– Super responders to IMiDs
8
Venetoclax in t(11;14) MM
200
150
100
mg
/dL
0
50
Generalized normal highGeneralized normal high
Generalized normal lowGeneralized normal low
Kappa FLC
A.K. Stewart, unpublishedKumar S et al. Blood. 2016;128: Abstract 488.
Pe
rce
nta
ge
of
Pa
tie
nts
ORR 21%
30
10
20
0
50
40ORR 40%
ORR 6%
All Patients(n=6)
t(11;14)(n=30)
Non-t(11;14) orundetermined
(n=36)
sCR CR VGPR PR
ORR by t(11;14) Status
3%3%
9%
6%
3%
7%
17%
13%3%3%
Imaging in Myeloma: IMAJEM (NCT01309334)
RVD × 3
RVD × 2
RVD × 5
Lenalidomide 1 year
Melphalan 200 mg/m2 + ASCT
CY (3g/m2) MOBILIZATIONGoal: 5 ×106 cells/kg
RVD × 3
CY (3g/m2)MOBILIZATIONGoal: 5 ×106 cells/kg
Randomize
Lenalidomide 1 year
ARM A ARM B
ASCT at relapse
PET-CT/MRI at diagnosis
PET-CT/MRI after 3 cycles
PET-CT/MRI before maintenance
N=134Moreau P et al. Blood. 2015;126: Abstract 395.
9
Imaging in Myeloma: IMAJEM (NCT01309334)
• At diagnosis– MRI was positive in 127/134 (94.7%)
– PET-CT in 122/134 (91%) patients (McNemar test = 0.94, P=0.33)
• MRI of the spine and pelvis and whole-body PET-CT are equally effective to detect bone involvement in symptomatic patients at diagnosis
Moreau P et al. Blood. 2015;126: Abstract 395.
Imaging in Myeloma: IMAJEM (NCT01309334)
• Univariate analysis for PFS/134 patients• Variables tested:
Gender, age, Ca, creatinine, ISS, response after 3 cycles of induction, response pre-maintenance, cytogenetics, MRI after 3 cycles, PET-CT after 3 cycles, MRI pre-maintenance, PET-CT pre-maintenance
• PET-CT after 3 cycles, P=0.04• PET-CT pre-maintenance, P<0.001• Response after 3 cycles (≥VGPR), P=0.04
Moreau P et al. Blood. 2015;126: Abstract 395.
10
PET-CT Normalization Before Maintenance Impact on PFS (62% Normalized)
Moreau P et al. Blood. 2015;126: Abstract 395.
P< 0.001
69%
51.6%
1.0
0.8
0.6
0.4
0.0
0.2
0 10 20 30
PET-CT -ve correlates with OS• Univariate analysis for OS/134 patients• Variables tested:
Gender, age, Ca, creatinine, ISS, response after 3 cycles of induction, response pre-maintenance, cytogenetics, MRI after 3 cycles, PET-CT after 3 cycles, MRI pre-maintenance, PET-CT pre-maintenance
• PET-CT pre-maintenance, P=0.003
Moreau P et al. Blood. 2015;126: Abstract 395.
11
69.9%
1.0
0.8
0.6
0.4
0.0
0.2
0 10 20 30
PET-CT Normalization Before Maintenance Impact on OS (62% Normalized)
P=0.003
94.6%
Moreau P et al. Blood. 2015;126: Abstract 395.
40
Conclusions• PET-CT and MRI are equally effective to detect bone
involvement in symptomatic patients at diagnosis
• MRI is not a good imaging method during follow-up
• PET-CT after 3 cycles of RVD and pre-maintenance is a powerful prognostic marker for PFS
• PET-CT pre-maintenance is a powerful prognostic marker for OS
12
Genomic Landscape in MM
Walker BA et al. J Clin Oncol. 2015;33:3911.Lonial S et al. Blood. 2014;124: Abstract 722.
Keats JJ et al. Blood. 2012;120:1067.
Chapman MA et al. Nature. 2011;471:467.Bolli N et al. Nat Commun. 2014;5:2997.Lohr JG et al. Cancer Cell. 2014;25:91.
• >1000 whole-exome/genome sequences
• A limited set of genes is recurrently mutated in MM: KRAS, NRAS, TP53, DIS3, FAM46C, BRAF, TRAF3 results are predominantly obtained from newly-diagnosed MM
Figure 1, page 93
Lohr JG et al. Cancer Cell. 2014;25:91.
Myeloma Mutation Panel (M3P)• Recurrently mutated putative MM genes: FAM46C, TP53, DIS3• Actionable genes: RAS, BRAF, IDH1• Pathways: MAPK, Cereblon, MYC• Drug resistance: IMiDs, proteasome inhibitors, glucocorticoid• Copy-number changes and common translocations• Biallelic deletions of tumor suppressors• Sample purity measurement: J regions IGH, IGL-K and IGL-L
88 genes, 1,327 amplicons, 373 Kb
51% of genes shared with Foundation Hemepanel, 35% with Foundation ONE
Kortuem KM et al. Blood. 2015;126: Abstract 1795.Hofste op Bruinink D et al. Blood. 2015;126: Abstract 2984.
Kortüm KM et al. Blood. 2016;128:1226.
13
Most Mutations Are Subclonal
Figure 1
Kortuem KM et al. Blood Cancer J. 2016;26:e397.
Myeloma-Specific Gene Mutation Panel Tracks Clonal Changes Over Time
Patient One Patient Two Patient Three
26.1 26.2 44.1 44.2 77.1 77.2
FAM46C 24% 92% 88%
FAT1 73%
KRAS 28% 60% 53%
SP140 48% 37% 85% 23%
SPEN 18%
TP53
24% 92% 82% 94%
78%
88%
Kortuem KM et al. Ann Hematol. 2015;94:1205.
14
Impact of Mutation on Myeloma Survival
Figure 4, page 3916
Walker BA et al. J Clin Oncol. 2015;33:3911.
Figure 3, page 3913
Walker BA et al. J Clin Oncol. 2015;33:3911.
Mutations in the Cereblon Pathway in at Least 26% of Relapsed/Refractory Patients
• In a patient refractory to Len/Dextherapy we identified mutations in both CRBN and IRF4
• One patient had 4 different CRBNmutations
• Probably higher as we did not look for structural change on chromosome 3
• 4 out of 5 IRF4-mutated patients shared a K123R variant
CRBN 1
CUL4B 1 1
IKZF3 1 1 1
IRF4 1 1 1 1 1
*gene found mutated in cohort
IRF4MYC
MM cytotoxicity
CRBNIMiDs
IKZF1/3
*
*
*
*DDB1
CUL4
ROC1
Kortüm KM et al. Blood. 2016;128:1226.
15
CoMMpass Enrollment• 1,000+ patients enrolled from >90 sites worldwide, with
over 850 samples molecularly profiled at baseline and >100 sequentially
CoMMpass: Triplets versus DoubletsEarly data suggests that patients on a triplet regimen (for ex. Bor-Len-Dex) appear to be doing better than those on a doublet (ex. Bor-Dex or Len-Dex)
16
CoMMpass: High Risk DiseaseIntegrative analyses using CoMMpass data will help identify patients at
greater risk of progression upfront and optimize their treatment
CoMMpass MMRF2172 CoMMpass MMRF2250
Age 72 71
Ethnicity Caucasian Caucasian
ISS stage II II
Baseline treatment VRD VRD
Cytogenetics t(4;14), del13, del17p t(4;14), del13, del17p
Time to progression (mos) 1 >18
p53 status mutated WT
MM cells in blood (%) 1.7 0
Circulating MM cells 36,648 614
Finding New Treatment OptionsBy looking closely at the molecular changes happening at progression, one can
identify potential new therapeutic options (for ex. a BRAF inhibitor here)
17
Summary• Revised ISS can assist therapeutic decision making• PET-CT normalization is also predictive• Clinical mutation panels now available
– Clonal depth of mutation– Actionable mutation– Prognosis– Drug resistance
• CoMMpass study largest genomics cohort in cancer, leading to precision therapy trials
– Additional CoMMpass data to be presented Saturday, 12/3 at 2:00PM
Making Sense of Frontline Options for Transplant Ineligible Patients
Thierry Facon, MDProfessor of Haematology
Department of HaematologyLille University Hospital
Lille, France
18
Patient Case• 75-year-old patient• Significant previous medical history• No significant previous surgical history• Physical examination: normal• Lytic bone disease• Impaired renal function• Revised ISS stage II
The patient is an ELDERLY patient with comorbidities, but good performance status.
He needs treatment.
The Transplant Eligibility Discussion (1)
• Patient is considered transplant candidate and so needs induction-ASCT with or without consolidation and maintenance
• Patient is (most likely) not a transplant candidate and needs conventional treatment
19
The Transplant Eligibility Discussion (2)• ASCT remains a standard of care for patients ≤65 years
of age in most countries – IFM 2009 and EMN studies1,2
• No large phase 3 randomized study has established the role of ASCT in elderly patients in the era of novel agents
• ASCT (single or even double) is routinely performed in some countries/centers for elderly patients between 65 and 75 years of age
1. Attal M et al. Blood. 2015;126: Abstract 391.2. Gay F et al. Blood. 2015;126: Abstract 392.
IFM 99-06 Study ProtocolNewly Diagnosed MM Patients 65–75 Years
Time From Randomization (month)
Pro
po
rtio
n
Treatment O/NSurvival time
median ± se (month)MP 97/196 32.2 ± 4.2
MP-T 43/125 53.6 ± 5.2
MEL100 66/126 38.6 ± 3.4
Arm MP
MP 1
MP 2
MP 3
MP 12
Arm MEL100
VAD 1
VAD 2
Cyclophosphamide 3g/m2 + lenograstim
+ PBSC harvest
MEL 100 mg/m2
+ PBSC + lenograstim
MEL 100 mg/m2
+ PBSC + lenograstim
Arm MP-T
MP
+
Thalidomide
400 mg/d
Overall Survival According to Treatment
Facon T et al. Lancet. 2007;370:1209.
0
0.2
0.4
0.6
0.8
1
0 12 24 36 48 60 72
20
A Phase III Trial Evaluating Conventional Dose Combination Immunochemotherapy With Ixazomib-Lenalidomide-Dexamethasone and Daratumumab (IRD2) to High-Dose Treatment With ASCT in the
Initial Management of Fit MM Patients Aged 65–75.
IRD2 IRD2IRD2 Collection IRD2 IRD2IRD2 IRD2IRD2 DR maintenance
IRD2 IRD2IRD2 Collection ASCT IRD2IRD2 DR maintenance
Arm A
Arm B
IFM 2017 Study
MPT and VMP Become Standards of Care (2008)
Facon T et al. Lancet. 2007;370:1209. Fayers PM et al. Blood. 2011;118:1239.
San Miguel JF et al. N Engl J Med. 2008;359: 906.
21
FIRST (IFM2007-01/MM-020): Study Design
1. Benboubker L et al. N Engl J Med. 2014;371:906. 2. Facon T et al. Lancet. 2007;370:1209.
3. Hulin C et al. J Clin Oncol. 2009;27:3664.Avet-Loiseau H et al. Blood. 2015;126: Abstract 730.
Pts aged >75 yrs: LoDEX 20 mg D1, 8, 15 & 22/28; MEL 0.2 mg/kg D1–4; THAL 100 mg D1–42/42.All pts received thromboprophylaxis.
• Stratification: age, country, and ISS stage
Arm BRd18
Arm CMPT
LEN + LoDEX 18 Cycles (72 wks) LENALIDOMIDE 25 mg D1-21/28LoDEX 40 mg D1, 8, 15 & 22/28
MEL + PRED + THAL 12 Cycles2,3 (72 wks)MELPHALAN 0.25 mg/kg D1-4/42PREDNISONE 2 mg/kg D1-4/42THALIDOMIDE 200 mg D1-42/42
Active Treatment + PFS Follow-Up Phase
LEN + LoDEX ContinuouslyLENALIDOMIDE 25 mg D1-21/28LoDEX 40 mg D1, 8, 15 & 22/28
Arm ARd Continuous
LT Follow-Up
PD
or
Un
acce
pta
ble
To
xici
ty
PD
, O
S, a
nd
Su
bse
qu
ent
AM
T
Screening
RA
ND
OM
IZA
TIO
N 1
:1:1
Hazard ratio Rd vs MPT: 0.69; P<0.001Rd vs Rd18: 0.71; P<0.001Rd18 vs MPT: 0.99; P=0.866
IFM 2007-01 FIRST Trial: PFS and OS
1. Lenalidomide European Public Assessment Report. March 2015. 2. Facon T et al. J Clin Oncol. 2015;33: Abstract 8524.
0 6 12 18 24 30 36 42 48 54 60 66 72
1.0
0.8
0.6
0.4
0.2
0
Su
rviv
al
Pro
ba
bili
ty
PFS (months)
Data cut-off: 3 March 2014Median follow-up: 45.5 mos
33%
14%
13%
Median PFS
Rd (n = 535) 26.0 mos
Rd18 (n = 541) 21.0 mos
MPT (n = 547) 21.9 mos
PFS as per investigator assessment1
Hazard ratio Rd vs MPT: 0.75; P=0.002Rd vs Rd18: 0.91; P=0.30
OS (months)
OS2
Data cut-off: 3 March 2014Median follow-up: 45.5 mos697 deaths (43% of ITT)
Median OS 4-year OS
Rd (n = 535) 58.9 mos 60%
Rd18 (n = 541) 56.7 mos 57%
MPT (n = 547) 48.5 mos 51%
0 6 12 18 24 30 36 42 48 54 60 66
1.0
0.8
0.6
0.4
0.2
0
Su
rviv
al
Pro
ba
bil
ity
72
22
IFM 2007-01, FIRST Trial: Age Analysis, OS
MPT, melphalan, prednisone, thalidomide; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles. Hulin C et al. Haematologica. 2015;100: Abstract S429.
RdRd18MPT
186193188
10810694
888372
704954
573137
442326
271520
1277
443
000
136137125
RdRd18MPT
349348359
311309306
295287291
272265262
249246244
231229223
171164161
1109988
554941
12138
329328330
000
Age ≤75 Years Age >75 YearsMedian, months
4-yr, %
Rd continuous 60.9 64
Rd18 60.6 61
MPT 55.3 57
Median follow-up of 45.5 months as of 3 March 2014
Hazard ratio (95% CI)Rd vs MPT: 0.76 (0.60–0.96)Rd vs Rd18: 0.90 (0.71–1.15)Rd18 vs MPT: 0.84 (0.66–1.06)
Pa
tie
nts
(%
)
100
80
60
40
20
0
OS (months)0 6 12 18 24 30 36 42 48 54 60 66
Hazard ratio (95% CI)Rd vs MPT: 0.72 (0.54–0.96)Rd vs Rd18: 0.91 (0.68–1.22) Rd18 vs MPT: 0.79 (0.60–1.04
Pa
tie
nts
(%
)
100
80
60
40
20
0
OS (months)0 6 12 18 24 30 36 42 48 54 60 66
Median, months
4-yr, %
Rd continuous 52.3 52
Rd18 45.7 48
MPT 37.8 39
After induction
After induction
SWOG S0777: Study Design
Durie B et al. Blood. 2015;126: Abstract 25.
RandomizationN = 525
Stratification:• ISS (I, II, III)• Intent to
transplant at progression (yes/no)
RandomizationN = 525
Stratification:• ISS (I, II, III)• Intent to
transplant at progression (yes/no)
Rd maintenance until PD, toxicity,
or withdrawal
• All patients received aspirin 325 mg/day• VRd patients received HSV prophylaxis
Eight 21-day cycles of VRdBortezomib 1.3/mg2 IVDays 1, 4, 8, and 11Lenalidomide 25 mg/day PODays 1–14Dexamethasone 20 mg/day PODays 1, 2, 4, 5, 8, 9, 11, 12
Eight 21-day cycles of VRdBortezomib 1.3/mg2 IVDays 1, 4, 8, and 11Lenalidomide 25 mg/day PODays 1–14Dexamethasone 20 mg/day PODays 1, 2, 4, 5, 8, 9, 11, 12
Six 28-day cycles of RdLenalidomide 25 mg/day PODays 1-21Dexamethasone 40 mg/day PODays 1, 8, 15, 22
Six 28-day cycles of RdLenalidomide 25 mg/day PODays 1-21Dexamethasone 40 mg/day PODays 1, 8, 15, 22
Lenalidomide 25 mg PO days 1–21
Dexamethasone 40 mg PO days 1, 8,15, 22
Lenalidomide 25 mg PO days 1–21
Dexamethasone 40 mg PO days 1, 8,15, 22
a National Cancer Institute program
23
SWOG S0777: PFS and OS by Assigned Treatment Arm
HR = 0.712 (0.560, 0.906)*Log-rank P value = 0.0018 (one sided)*
HR = 0.709 (0.516, 0.973)*Log-rank P value = 0.0250 (two sided)*
* Stratified
Months From Registration
0
10
20
30
40
50
60
70
80
90
100
Pat
ien
ts (
%)
0 24 48 72 96
PFS by assigned treatment arm
Events/NMedian in months
VRd 137/242 43 (39, 52)
Rd 166/229 30 (25, 39)
OS by assigned treatment arm
Rd
VRdRdVRd
Durie B et al. Blood. 2015;126: Abstract 25.
a National Cancer Institute program
Months From Registration
0
10
20
30
40
50
60
70
80
90
100
Pat
ien
ts (
%)
0 24 48 72 96
Events/NMedian in months
VRd 76/242 75 (66, -)
Rd 100/229 64 (56, -)
Combination Study of Carfilzomib, Lenalidomide, and Dexamethasone in Patients With NDMM: Study Design
Key inclusion criteria
• Age ≥18 years
• NDMM with measurable disease
• Creatinine clearance ≥60 mL/min
• ECOG PS 0–2
• ANC ≥1.0 × 109/L, hemoglobin ≥8.0 g/dL, platelet count ≥75 × 109/L
• Adequate hepatic function
KRdCarfilzomib
20/36 mg/m2 IV, days 1, 2, 8, 9, 15, 16Cycle 1, days 1, 2: carfilzomib dose 20 mg/m2
Lenalidomide25 mg/day PO, days 1–21
Lenalidomide was administered on days 2–21 in cycle 1 alone and on days 1–21 of cycles 2–8
Dexamethasone20/10 mg IV or PO, days 1, 2, 8, 9, 15, 16, 22, 23
Cycles 1–4: dexamethasone dose 20 mg; cycles 5–8: dexamethasone dose 10 mg.
Lenalidomide10 mg/day PO,
days 1–21
If ≥SD
Eight 28-day cyclesStem cell harvest after 4 cycles of KRd
for transplant-eligible patientsExtended dosing
24 cycles
Korde N et al. JAMA Oncol. 2015;1:746.
Primary end point
• Rate of PN grade ≥ 3
Secondary end point
• MRD*
• Response rates
• Progression-free survival
• Duration of response
• Safety
*Assessed at the following time points: baseline, achievement of a CR and/or at the completion of cycles 8, 20, and 32, and at termination of protocol therapy.
24
Combination Study of Carfilzomib, Lenalidomide, and Dexamethasone in Patients With NDMM: Efficacy
Table 3, page 50
Korde N et al. JAMA Oncol. 2015;1:746.
What about the evaluation of frailty?
Do we need specific studies for frail patients?
25
FIRST (MM-020): Frailty Analysis-Frailty Algorithm
• Patients were categorized into three severity groups (fit, intermediate, frail) as described by a proxy algorithm based on the IMWG frailty scale1
1. Palumbo A et al. Blood. 2015;125:2068.Facon T et al. Blood. 2015;126: Abstract 4239.
IMWG Frailty Scale1 Proxy for MM-020 Analysis ScoreAge
≤75 yrs76−80 yrs>80 yrs
Age≤75 years76−80 yrs>80 yrs
012
Activity of Daily Living score>4≤4
EQ-5D: Self Care score1 (no problem)2−3 (moderate or severe problem)
01
Instrumental Activity of Daily Living score5≤5
EQ-5D: Usual Activities score1 (no problem)2−3 (moderate or severe problem)
01
Charlson Comorbidity Index score≤1≥2
Charlson Comorbidity Index score≤1≥2
01
Total0: Fit1: Intermediate≥2: Frail
FIRST (MM-020): Frailty Analysis PFS and OS by Severity Group With ISS Stage
• No treatment effects seen in these groups, likely due to small patient numbers
Facon T et al. Blood. 2015;126: Abstract 4239.
Severity n Median PFS, mos (95% CI) HR (95% CI)Fit + ISS I 84 34.1 (25.6-43.7)
0.71 (0.50-0.99)Fit + ISS II/III 171 23.3 (21.2-30.2)Int + ISS I/II 298 27.7 (24.6-30.4)
0.63 (0.49-0.80)Int + ISS III 150 19.2 (17.6-21.3)Frail + ISS I/II 437 23.0 (20.5-25.8)
0.69 (0.58-0.82)Frail + ISS III 377 17.1 (14.1-19.0)
Severity n Median OS, mos (95% CI) HR (95% CI)
Fit + ISS I 84 NR0.57 (0.33-1.00)
Fit + ISS II/III 171 NR
Int + ISS I/II 298 63.1 (58.2-NR)0.43 (0.32-0.59)
Int + ISS III 150 44.3 (33.5-56.1)
Frail + ISS I/II 437 58.9 (49.5-NR)0.57 (0.47-0.69)
Frail + ISS III 377 35.6 (32.5-40.6)
00
0.2
0.4
0.6
0.8
1.0
20 40 60 80PFS By Investigator, mos
Su
rviv
al P
rob
abili
ty
00
0.2
0.4
0.6
0.8
1.0
20 40 60 80OS, mos
Su
rviv
al P
rob
abili
ty
26
UKMRA Myeloma XIV: FITNESSFrailty-Adjusted Therapy In Transplant
Non-Eligible PatientS With Symptomatic Myeloma
First-line therapy in the nonintensive setting for myeloma
CI: Prof Graham Jackson & Prof Gordon Cook
Frailty index–adjusted therapy
1:1
1:2 FIT
C – 500 mg D1 & D8 R – 25 mg D1–21 D – 20 mg I – 4 mg weekly
UNFIT FRAIL
1:2
CRDa IRDa
1:2
CRDa IRDa
1:2
CRDa IRDa
TREAT TO MAXIMUM RESPONSE (6–8 cycles)
FIT: C – 500 mg D1 & D8, R – 25 mg D1-21, D – 20 mg/wk, I – 4 mg/wkUNFIT: C – 350 mg D1 & D8, R – 15 mg D1-21, D – 10 mg/wk, I – 3 mg/wkFRAIL: C – 250 mg D1 & D8, R – 10 mg D1-21, D – 10 mg/wk, I – 3 mg/wk
1:1
Lenalidomide Ixazomib/Lenalidomide
MA
INT
EN
AN
CE
IND
UC
TIO
N
Trial designTransplant-ineligible NDMM
Non-adjusted
CRDa IRDa
REACTIVE ADAPTIVE
Frailty indexing (FI) performed in all patients at baseline
27
Treatment of MM in Elderly Patients: Landscape and Perspectives
1. DaraVMP vs. VMP. Available at: https://clinicaltrials.gov/ct2/show/NCT021954792. Durie B et al. Blood. 2015;126: Abstract 25.
3. O’Donnell EK et al. Blood. 2015;126: Abstract 4217. 4. IRD vs RD (Tourmaline 2). Available at: https://clinicaltrials.gov/ct2/show/NCT01850524. 5. EloRD vs RD (Eloquent 1). Available at: https://clinicaltrials.gov/ct2/show/NCT01335399.
6. DaraRD vs. RD. Available at: https://clinicaltrials.gov/ct2/show/NCT02252172. 7. KMP vs. VMP (Clarion). Available at: https://clinicaltrials.gov/ct2/show/NCT01818752.
8. Mateos MV et al. Blood. 2016;127:420.
MP
VMP
MPT
MPR-R
# Vd
MPT-T
<
<
<
Rd
?
<
VMP – Daratumumab1
VRD2,3
Rd – Ixazomib4
Rd – Elotuzumab5
Rd – Daratumumab6
MP – Carfilzomib7
Alternating regimens8 ?
Phase 3 Rd-Based Continuous Studies for Elderly Patients
• Primary end point for all studies is PFS1. EloRD vs RD (Eloquent 1). Available at: https://clinicaltrials.gov/ct2/show/NCT01335399. 2. IRD vs RD (Tourmaline 2). Available at: https://clinicaltrials.gov/ct2/show/NCT01850524.
3. DaraRD vs. RD. Available at: https://clinicaltrials.gov/ct2/show/NCT02252172.
NCT01335399 NCT01850524 NCT02252172
Placebo + RR 10 mgUntil PD
Ixazomib+ RIxazomib: 3 mgR: 10 mg
Until PD
DEX Discontinued
ELO-RdELO: 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 28-d cycles; Rdfor up to 2 years;
DARA until PD
RdR: 25 mg PO ; D1–21DEX: 40 mg PO ; D1, 8, 15 & 2228-d cycles until PD
DARA-RdDARA: 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
RdR: 25 mg PO ; D1–21DEX: 40 mg PO ; D1, 8, 15 & 2228-d cycles until PD
Ixazomib-Rd Ixazomib: 4 mg R: 25 mg
DEX: 40 mg; D1, 8, 15 & 22
28-d cycles/18 mos
RdR: 25 mg PO ; D1–21DEX: 40 mg PO ; D1, 8, 15 & 2228-d cycles/18 mos
DEX Discontinued
Elotuzumab Ixazomib Daratumumab
28
Patient Case 2
Robert M. Rifkin, MDAssociate Chair – US Oncology Research
Disease Lead – Multiple MyelomaAttending Physician
Rocky Mountain Cancer CentersDenver, Colorado
Case Study 2• 52-year-old woman referred for workup of
anemia that proved to be iron deficiency. This was only partly corrected with oral iron supplementation. Due to her incomplete response to iron replacement, further workup was undertaken.
29
Case Study 252-year-old woman referred for workup of anemia.
• None
Past medical history
• Appendectomy and varicose vein stripping
Past surgical history
• Sister-in-law has myeloma and failed two SCTs
Familyhistory
• Married, works at a uniform supply firm
• Nonsmoker, rare social alcohol
• No substance use
Socialhistory
• Normal
• ROS: negative except for mild fatigue
Physicalexam
Case Study 2: LabsActualValue
Normal Range
CBC withdifferential
WBC (103/mL) 3.7 (4–11)
Hemoglobin (g/dL) 9.8 (13–16)
Hematocrit (%) 30.1 (34–45)
Platelets (103/mL)* 278 (150–400)
Neutrophils (103/mL) 5.6 (1.9–7.5)
CMP
BUN (mg/dL) 16 (7–20)
Creatinine (mg/dL) 0.8 (0.7–1.2)
Calcium (mg/dL) 8.6 (8.4–10.2)
Total protein (g/dL) 8.0 (6.3–8.2)
Albumin (g/dL) 3.4 (3.5–5.0)
SPEPIF- IgG
M protein spike (g/dL) 2.6
ActualValue
Normal Range
QuantitativeIgs + serum immuno-fixation
IgG (mg/dL) 3,431 (H) (700–1,600)
IgA (mg/dL) 158 (H) (70–400)
IgM (mg/dL) 40 (H) (40–230)
FLC
Kappa quant FLC (mg/L) 437.6 (H) (3.30–19.40)
Lambda quant FLC (mg/L) 13.67 (H) (5.71–26.30)
Kappa/lambda quant FLC ratio
31.9 (H) (0.26–1.65)
*With normal iron studies
30
Case Study 2: Imaging and BM Biopsy
Skeletal survey• Indeterminate
lesions in right intertrochanteric area
DEXA scan• Osteopenia
Boneimaging
• 40% cellular with 30% plasma cells
• Aspirate 24% plasma cells
BMbiopsy
• 2% events positive for CD38, CD56, CD138, and cytoplasmic kappa light chains
Flow cytometry
• 46, XX
Cytogenetics
• Negative for gain of 1q21
• Negative for loss of chromosome 13q
• Negative for loss of TP53 and ATM
• Negative for IgH (14q32) and IGH/CCND1 [t(11;14)] rearrangement
FISH*
*CD138 selected plasma cells
Strategies to Prolong Response
Amrita Y. Krishnan, MDProfessor, Department of Hematology & Hematopoietic Cell
TransplantationDirector, Judy and Bernard Briskin Center for Multiple Myeloma Research
City of Hope Medical CenterDuarte, California
31
Options to Prolong Remission• Increase depth of response
– High dose chemotherapy (single versus tandem)• EMN02,[1] BMT-CTN0702[2]
• Prolong therapy– Consolidation
• RVD: EMN02/HO95,[3] BMTCTN0702 Stamina2
• Zimmerman (KRd)4 Roussel (KRd)5
– Maintenance • Myeloma XI[6]
1. Cavo M et al. Blood. 2016;128: Abstract 991.2. Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1.
3. Sonneveld P et al. Blood. 2016;128: Abstract 242.4. Zimmerman T et al. Blood. 2016;128: Abstract 675.
5. Roussel M et al. Blood. 2016;128: Abstract 1142. 6. Jackson GH et al. Blood. 2016;128: Abstract 1143.
RVD, cycles 2, 3
RVD × 2RVD × 5
Lenalidomide (10–15 m/d) 12 mos
Melphalan 200 mg/m2 + ASCT
Induction
Consolidation
Maintenance
CY (3g/m2) + G-CSF MOBILIZATION
Goal: 5 ×106 cells/kg
RVD, cycles 2, 3
CY (3g/m2) + G-CSFMOBILIZATION
Goal: 5 ×106 cells/kg
Randomize, stratification ISS & FISH
PBSC collection
Lenalidomide (10–15 mg/d) 12 mos
SCT at relapse MEL 200 mg/m2 if <65 yrs,
≥65 yrs 140 mg/m2
IFM/DFCI 2009 Study Schema
Attal M et al. Blood. 2015;126: Abstract 391.
Registration, newly diagnosed MM pts 65 years (ASCT candidates)
ARM B: Early transplant armARM A: Late transplant arm
US len maintenance till progression
1 cycle RVD
32
Attal M et al. Blood. 2015;126: Abstract 391.
IFM 2009: Best ResponseRVD Arm
N=350Transplant Arm
N=350 P Value
CR (%) 49 59
0.02 VGPR (%) 29 29
PR (%) 20 11
<PR (%) 2 1
At least VGPR (%) 78 88 0.001
Neg MRD by FCM, n (%) 228 (65%) 280 (80%) 0.001
Attal M et al. Blood. 2015;126: Abstract 391.
IFM 2009: PFS (9/2015)
P<0.001
0102030405060708090
100
Pat
ien
ts (
%)
0 12 24 36 48Months of Follow-Up
HDTno HDT
N at riskHDT 350 309 261 153 27
no HDT 350 296 228 128 24
33
0102030405060708090
100
Pat
ien
ts (
%)
0 12 24 36 48Months of Follow-Up
HDTno HDT
N at riskHDT 350 328 309 226 55
no HDT 350 338 320 244 56
Attal M et al. Blood. 2015;126: Abstract 391.
IFM 2009: OS (9/2015)
P NS
RVD ArmN=48
TransplantN=54
Myeloma, n (%) 40/48 (83) 35/54 (65)
Toxicity, n (%) 4/48 (8) 9*/54 (16)
SPM, n (%) 1/48 (2) 6/54 (11)
Others, n (%) 3/48 (6) 4/54 (7)
*Including 5 transplant related deaths.
Attal M et al. Blood. 2015;126: Abstract 391.
IFM 2009: Cause of Death (9/2015)
34
Intensification Therapy with Bortezomib-Melphalan-Prednisone Versus Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma:
An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial)
VMP (n=497)
HDM (n=695) HR/OD (95% CI) P Value
Median PFS (mos) 44 NR ─ ─3-Yr PFS (%) 57.5 66 HR 0.73 (0.59-0.90) 0.003Probability of achieving ≥VGPR (%) 74 85.5 OD 1.90 (1.42-2.54) <0.001
Cavo M et al. Blood. 2016;128: Abstract 673.
Upfront HDM and ASCT significantly improved PFS and increased the rate of high quality responses.
R2
VMP4, 42-day cycles
CyBorD3-4, 21-day cycles HDM + Double ASCT
HDM + Single ASCTR1
RVD
No RVD
Len
InductionConsolidation Maintenance
High Dose Therapy: Single vs Tandem
Cavo M et al. Blood. 2016;128: Abstract 991.Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1.
VMP4, 42-day cycles
CyBorD3-4, 21-day cycles HDM + Double ASCT
HDM + Single ASCTR1
Register and Randomize
MEL 200mg/m2 VRD x 4
LenalidomideMaintenance
LenalidomideMaintenance
LenalidomideMaintenance
MEL 200mg/m2
ACM
AM
TAM
EMN02/HO95
Stamina
Median PFS (27-mos f/up):• ASCT1, 45 mos• ASCT2, NR
Estimated PFS (38-mos):• TAM, 56%• ACM, 57%• AM, 52%
35
0102030405060708090
100
Pa
tie
nts
(%
)
0 12 24 36 48Months of Follow-Up
0102030405060708090
100
Pa
tie
nts
(%
)
0 12 24 36 48Months of Follow-Up
RVD Arm Transplant Arm
Attal M et al. Blood. 2015;126: Abstract 391.Avet-Loiseau H et al. Blood. 2015;126: Abstract 191.
Increase Depth of Response: MRD
P<0.001
MRD posMRD neg
P<0.001
N at riskMRD pos 89 75 54 22 2MRD neg 140 135 113 72 14
MRD posMRD neg
N at riskMRD pos 65 57 43 30 4MRD neg 172 166 151 86 17
MRD: Still ??
Flow cytometry• Feasible in 100% of patients• Does not require diagnostic sample• Widely available/low cost
NGS (adaptive)• Sensitivity <10-6
• Frozen samples• Fully standardized
Advantages
Flow cytometry• Fresh sample (<24–48 h)• Sensitivity 10-4–10-5
• Lack of standardization (operator)
NGS (adaptive)• Requires diagnostic sample (clone
ID)• Feasibility
Disadvantages
Paiva B et al. Clin Cancer Res. 2015;21:2001.Nishihori T et al. Curr Hematol Malig Rep. 2016;11:118.
36
Sensitivity Matters
P value (trend): P<0.0001
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pa
tie
nts
Wit
ho
ut
Pro
gre
ss
ion
(%
)
40 40(0) 40(0) 40(0) 33(6) 23(9) 15(6) 4(4) 2(1)23 23(0) 23(0) 23(0) 22(1) 19(3) 14(2) 3(5) 2(0)29 29(0) 29(0) 29(0) 28(0) 22(5) 16(3) 4(4) 1(1)86 86(0) 86(0) 86(0) 86(0) 77(5) 61(3) 36(5) 10(0)
N at risk (events)
0 6 12 18 24 30 36 42 48
Months Since Randomization
MRD at post-maintenance
[10-4; 10-3][10-5; 10-4][10-6; 10-5]
<10-6
≥10-4
[10-5; 10-4][10-6; 10-5]
<10-6
Avet-Loiseau H et al. Blood. 2015;126: Abstract 191.
Association of MRD With Superior Survival Outcomes in Patients With Multiple Myeloma:
A Meta-Analysis
• 14 studies• MRD negativity correlated with PFS/OS• 5 trials included ASCT• PCR > MFC (sensitivity)• Only 1 study showed predictive value in unfavorable cytogenetics• 10 studies maintenance (2 post maintenance)
Munshi NC et al. JAMA Oncol. 2016. Sept 15 [Epub ahead of print].
37
IMWG Criteria for Response and MRD Assessment in MM
• MRD negativity in the marrow (NGF, NGS, or both) and by imaging as defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years)
Sustained MRD-negativeSustained MRD-negative
• Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher
Flow MRD-negativeFlow MRD-negative
• Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher
Sequencing MRD-negativeSequencing MRD-negative
• MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood pool SUV or decrease to less than that of surrounding normal tissue
Imaging plus MRD-negativeImaging plus MRD-negative
Kumar S et al. Lancet Oncol. 2016;17:e328.
Prolong Response: Consolidation
Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1.
Register and Randomize MEL 200mg/m2 VRD x 4 Lenalidomide
Maintenance
LenalidomideMaintenance
LenalidomideMaintenance
MEL 200mg/m2
N=750 pts (250 in each arm)
ACM
AM
TAM
ASCT with Len Maintenance
(AM)
Consolidation with Len Maintenance
(ACM)
Tandem ASCT with Len Maintenance
(TAM)
N 257 254 247
38-mo PFS (%) 52 57 56
BMT CTN 0702
38
Prolong Response: Consolidation
Sonneveld P et al. Blood. 2016;128: Abstract 242.
EMN02/HO95
R2
VMP4, 42-day cycles
CyBorD3-4, 21-day cycles HDM + Double ASCT
HDM + Single ASCTR1
RVD
No RVD
Len
InductionConsolidation Maintenance
ConsolidationNo
Consolidation P Value
3-year PFS (%) 65 60 0.045
Not retained in high risk cytogenetics (0.91)
Prolong Response: Consolidation
KRd ASCT KRd KRdIndefinite
Maintenance Lenalidomide
Induction (Cycles 1–4)
Consolidation (Cycles 5–8)
Maintenance (Cycles 9–18) Post
SCTPost KRdConsol
Post KRdMaint
MRD (%) MFC/NGS -- 82/66 90/71
sCR (%) 20 69 82
1. Zimmerman T et al. Blood. 2016;128: Abstract 675.2. Roussel M et al. Blood. 2016;128: Abstract 1142.
KRd ASCT KRdLenalidomide,
1 Year
Induction (Cycles 1–4)
Consolidation (Cycles 5–8) Maintenance
Post Induction
(n=46)Post ASCT
(n=42)
Post Consol(n=42)
MRD (%) by flow 63 81 89
CR + sCR (%) 26 45 69
ORR (%) 98 98 98
Phase 2 US Study1
Phase 2 IFM Study2
KRd is now being compared with VRd in a randomized clinical trial.
39
Prolonging Response: Maintenance
• What is the optimal drug?• What is the optimal duration of maintenance?• What is the benefit of maintenance?
• Ultimate goal; prolonged survival
Maintenance Therapy Post SCT: What Is Known
• Bortezomib maintenance; HOVON1
• Lenalidomide maintenance after ASCT reduces the risk of progression or death by approximately 50%2-5
• All phase 3 studies had progression-free survival as the primary end point
1. Sonneveld P et al. J Clin Oncol, 2012;30:2946.2. Palumbo A et al. N Engl J Med. 2014;371:895.
3. McCarthy PL et al. N Engl J Med. 2012;366:1770. 4. Attal M et al. N Engl J Med. 2012;366:1782.
5. Palumbo A et al. N Engl J Med. 2012;366:1759.
40
Randomization
MM Stage II or III, Age 18–65
CAD + GCSF
3 × VAD
CAD + GCSF
3 × PAD
MEL 200 + PBSCT
In GMMG 2nd
MEL 200 + PBSCT
MEL 200 + PBSCT
In GMMG 2nd
MEL 200 + PBSCT
Thalidomide maintenance50 mg/day for
2 years
Allogeneic transplant
Bortezomib maintenance
1.3 mg/m2/2 weeks for 2 years
Bortezomib 1.3 mg/m2
i.v., 2x/w
Doxorubicin 9 mg/m2
Dexameth 40 mg
HOVON Study Schema
Sonneveld P et al. J Clin Oncol, 2012;30:2946.
OS by Treatment Arm
• OS at 96 m: 48% vs 45%
• HR: 0.87, 95% CI0.71–1.04; P=0.22
• RMST8y: 4.8 months (95% CI 0.2–9.5; P=0.04)
Sonneveld P et al. Blood. 2015;126: Abstract 27.
A: VAD
B: PAD
0
25
50
75
100
Cu
mu
lati
ve P
erce
nta
ge
Months0 24 48 72 96
Overall SurvivalRandomization Arm
N D
A: VAD 414 217
B: PAD 413 204
Cox LR Stratified P=0.22
41
Studies Included in Meta-Analysis
Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT
CALGB 100104(accrual 8/2005–11/2009)
INDUCTIONASCT
1:1 RANDOMIZATION“NO EVIDENCE OF PD”
LEN MNTCa
(n=231)PLACEBO
(n=229)
INTERIM ANALYSIS AND UNBLINDING
Dec 2009
CROSSOVER BEFORE PD ALLOWED
CONTINUEDTREATMENT
a Starting dose of 10 mg/day on days 1–28/28 was increased to 15 mg/day if tolerated and continued until PD. b Patients received maintenance 10 mg/day on days 1–21/28 until PD.
GIMEMA (RV-MM-PI-209)(accrual 11/2007–7/2009)
CONTINUEDTREATMENT
LEN MNTCb
(n=67)NO TREATMENT
(n=68)
CONTINUED TREATMENT
LEN MNTCbNO TREATMENT
PRIMARY ANALYSIS
2 × 2 DESIGNLEN + DEX × 4
INDUCTION
ASCT MPR: 6 COURSES
Attal M et al. J Clin Oncol. 2016;34: Abstract 8001.
IFM 2005-02(accrual 6/2006–8/2008)
INTERIM ANALYSIS AND UNBLINDING
Dec 2009 Jan 2010
NO CROSSOVER BEFORE PD ALLOWED
CONTINUED TREATMENT
ALL TREATMENT DISCONTINUED
Jan 2011
LEN MNTCa
(n=307)PLACEBO
(n=307)
LEN: 2 COURSES
INDUCTIONASCT
1:1 RANDOMIZATION“NO EVIDENCE OF PD”
Overall Survival: Median Follow-Up of 80 Months
There is a 26% reduction in risk of death, representing an estimated 2.5-year increase in median survival.a
N=1,209 Lenalidomide Control
Median OS(95% CI), mos
NE(NE–NE)
86.0(79.8–96.0)
HR (95% CI)P value
0.74 (0.62–0.89)0.001
a Median for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74).
0.00 10 20 30 40 50 60 70 80 90 100 110 120
0.2
0.4
0.6
0.8
1.0
605 578 555 509 474 431 385 282 200 95 20 1 0604 569 542 505 458 425 350 271 174 71 10 0
Overall Survival, mos
Su
rviv
al
Pro
bab
ility
Patients at risk
7-yr OS
62%
50%
Attal M et al. J Clin Oncol. 2016;34: Abstract 8001.
42
Cumulative Incidence of Second Primary Malignancies
a HR based on Cox proportional hazards model. b P value is based on log-rank test.
586 559 514 465 422 365 251 139 38 1 586 554 508 458 415 360 251 136 35 0602 559 525 468 428 340 248 119 28 0 602 559 520 461 417 328 241 117 28 0
Time to Hematologic SPM Onset, mos Time to Solid Tumor SPM Onset, mos
LenalidomideControl
HR (95% CI): 2.03a (1.14–3.61)P=0.015b
LenalidomideControl
HR (95% CI): 1.71a (1.04–2.79)P=0.032b
Hematologic Solid Tumor
Patients at risk
Patients at risk
0 12 24 36 48 60 72 84 96 1080.0
Cu
mu
lati
ve I
nci
de
nce
0.20
0.40
0.60
0.80
1.00
0 12 24 36 48 60 72 84 96 1080.0
Cu
mu
lati
ve I
nc
ide
nc
e
0.20
0.40
0.60
0.80
1.00
Attal M et al. J Clin Oncol. 2016;34: Abstract 8001.
Lenalidomide is Highly Effective Maintenance Therapy in MM: Phase 3 Myeloma XI study
• Lenalidomide continued to disease progression versus no therapy in both newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) populations
• Hematologic second primary malignancy 0.9% with maintenance vs 0.3% with no maintenance
Jackson G et al. Blood. 2016;128: Abstract 1143.
TE (n=828) TNE (n=722)
P ValueMaint No Maint Maint No Maint
Median PFS (mos) 60 28 26 12 <0.0001
43
Ultimate Goal: Prolong Survival• High dose therapy (IFM/DFCI, EMN02, BMTCTN)• Consolidation (EMN02, BMTCTN)• Maintenance
– Lenalidomide: Estimated 2.5-year improvement in median overall survival
– Bortezomib: Estimated 5-month improvement in overall survival
Future: MRD-directed therapy
Panel Discussion
44
Patient Case 3
Robert M. Rifkin, MDAssociate Chair – US Oncology Research
Disease Lead – Multiple MyelomaAttending Physician
Rocky Mountain Cancer CentersDenver, Colorado
Case Study 3• 73-year-old man with a 7-year history of IgG kappa MGUS• Experiences evolution of disease to symptomatic myeloma:
– IgG has increased to 7,233 mg/dL– Hgb has fallen to 8.5 gm/dL– Bone marrow is 60% cellular with 50% plasma cells that are
CD138(+) – Marrow cytogenetics shows 46,XY – Myeloma FISH panel is negative
• The patient is placed on lenalidomide and dexamethasone – Achieves VGPR after 2½ years of therapy– Stops this due to diarrhea and asthenia
45
Case Study 3• Patient becomes anemic again after being off of therapy
for 9 months • He then moves to Colorado, where he reports dyspnea
that he feels is due to the altitude– IgG is 8592 mg/dL– Hgb is 8.0 gm/dL– Bone marrow biopsy shows 75% cellularity with 80% plasma
cells, some in sheets – Conventional cytogenetics are normal – FISH panel shows new del17p
Case Study 3• The patient elects to begin therapy with carfilzomib and
dexamethasone; refuses further lenalidomide • After two cycles, the patient presents with dyspnea; a
cardiac echo shows a LVEF of 40%• Patient also notes left tibial pain; a plain x-ray shows a
destructive lesion• Patient undergoes surgery to place an IM rod in his left
femur following treatment of his presumed carfilzomib cardiomyopathy
• Patient now returns to clinic to discuss his next therapy after completion of five fractions of radiation to his tibia
46
Case Study 3: LabsActualValue
Normal Range
CBC withdifferential
WBC (103/mL) 3,400 (4–11)
Hemoglobin (g/dL) 9.9 (13–16)
Hematocrit (%) 31.6 (34–45)
Platelets (103/mL) 164 (150–400)
Neutrophils (103/mL) 2.1 (1.9–7.5)
CMP
BUN (mg/dL) 24 (7–20)
Creatinine (mg/dL) 0.85 (0.7–1.2)
Calcium (mg/dL) 7.6 (8.4–10.2)
Total protein (g/dL) 10.6 (6.3–8.2)
Albumin (g/dL) 1.7 (3.5–5.0)
SPEPIF- IgG
M protein spike (g/dL) 4.5
ActualValue
Normal Range
QuantitativeIgs + serum immuno-fixation
IgG (mg/dL) 8,431 (H) (700–1,600)
IgA (mg/dL) <30 (L) (70–400)
IgM (mg/dL) <5 (L) (40–230)
FLC
Kappa quant FLC (mg/L) 760.4 (H) (3.30–19.40)
Lambda quant FLC (mg/L) 13.67 (H) (5.71–26.30)
Kappa/lambda quant FLC ratio
55.62 (H) (0.26–1.65)
New Agents, Classes in the Relapsed Setting
Faith E. Davies, MBBCh, MRCP, MD, FRCPathProfessor of Medicine
Medical Director, Myeloma InstituteUniversity of Arkansas for Medical Sciences
Little Rock, Arkansas
47
Factors Affecting Treatment Decisions in RRMM
*IMiD-based, proteasome-based, alkylators, dexamethasone.
Salvage therapies
Class of prior therapy*; degree of response to prior therapy;
PFS; tolerability of prior therapy
(treatment-related AEs)
Patient-related factors: age, PS, counts, PN, VTE, RI, cytogenetic
profile, extramedullary involvement,
etc
Aggressiveness of disease and
prognostic features
Number and degree of
relapses and refractory disease
Disease progression
First-line therapy
Current Therapies for RRMM 1–3 Lines Can Be Classified by the Drug’s Mechanism of Action
BortezomibProteasome inhibitors Carfilzomib Ixazomib
ThalidomideImmunomodulators Lenalidomide Pomalidomide
PanobinostatHistone deacetylase
DaratumumabMonoclonal antibodies Elotuzumab
High-dose melphalanAlkylators Bendamustine Cyclophosphamide
DexamethasoneSteroids Prednisolone Methyl prednisolone
Critical to understand treatment patterns specific to your own country/region as
drug approval variability exists
48
Two Important Questions• Which drugs do I use in the combination?
– Individualize the drug choice toward the specific patient
– Take advantage of different mechanisms of action
• How many drugs should I use?– Aim for a triplet– Monitor closely and mange the side effects– Staying on treatment is the key
Two Important Questions• Which drugs do I use in the combination?
– Individualize the drug choice toward the specific patient
– Take advantage of different mechanisms of action
• How many drugs should I use?– Aim for a triplet– Monitor closely and mange the side effects– Staying on treatment is the key
49
Plethora of New Randomized Studies to Help Guide Treatment Decisions
Control Arm Comparator Arm Trial Name
Lenalidomide and dexamethasone
Carfilzomib, lenalidomide, and dexamethasone ASPIRE
Elotuzumab, lenalidomide, and dexamethasone
ELOQUENT 2
Ixazomib, lenalidomide, and dexamethasone TOURMALINE 1
Bortezomib and dexamethasone
Carfilzomib and dexamethasone ENDEAVOR
Panobinostat, bortezomib, and dexamethasone PANORAMA 1
Dexamethasone Pomalidomide and dexamethasone MM03 NIMBUS
No transplant High-dose melphalan Myeloma X
Study N Treatment
ASPIRE1 792Carfilzomib-lenalidomide-dexamethasone (KRd) vs lenalidomide-dexamethasone (Rd)
ELOQUENT-22 646Elotuzumab-lenalidomide-dexamethasone (Erd) vs lenalidomide-dexamethasone (Rd)
TOURMALINE-MM13 722Ixazomib-lenalidomide-dexamethasone (Ird)vs placebo-lenalidomide-dexamethasone (Rd)
ENDEAVOR4 929Carfilzomib-dexamethasone (Kd)vs bortezomib-dexamethasone (Vd)
Differences Between Studies in Baseline Characteristics
1. Stewart AK et al. N Engl J Med. 2015;372:142.2. Lonial S et al. N Engl J Med. 2015;373:621.
3. Moreau P et al. N Engl J Med. 2016;374:1621.4. Dimopoulos MA et al. Lancet Oncol. 2016;17:27.
Proportion of patients with refractory disease, disease stage ISS III, low creatinine clearance, high risk cytogenetics
50
ASPIRE: Carfilzomib-Lenalidomide-Dexamethasone (KRd) vs Lenalidomide-Dexamethasone (Rd)
• Phase 3, open-label, randomized, multicenter study
N=792RRMM patients
• Prior treatment with 1–3 regimens
• ≥ PR to ≥1 prior regimen
RdLEN: 25 mg, d 1–21DEX: 40 mg, d 1, 8, 15, 2228-day cycles until progression
KRdCFZ: 27 mg/m2, d 1, 2, 15, 16LEN: 25 mg, d 1–21DEX: 40 mg, d 1, 8, 15, 22Six 28-day cycles
*Carfilzomib is administered at 20 mg/m2 on Days 1 and 2
• Stratified for previous Bortezomib therapy• Patients received antiviral and antithrombotic prophylaxis• Primary end point: PFS • Secondary end points: OS, ORR, DoR, HRQoL, safety
KRdCFZ: 20/27 mg/m2, d 1–2*, 8–9, 15–16LEN: 25 mg, d 1–21DEX: 40 mg, d 1, 8, 15, 22Twelve 28-day cycles
RdLEN: 25 mg, d 1–21DEX: 40 mg, d 1, 8, 15, 22Until PD
Stewart AK et al. N Engl J Med. 2015;372:142.
17.226.3
38.131.1
17.75.1
14.1
4.3
0
20
40
60
80
100
KRd(n=396)
Rd(n=396)
Pa
tie
nts
, %
Response rates sCRCRVGPRPR
ORR: 87.1%
ORR: 66.7%
≥PR, ≥VGPR and ≥CR: P<0.001
ASPIRE: KRd vs RdEfficacy
• Median follow-up was 32.3 months for KRd and 31.5 months for Rd
• PFS benefit for KRd was observed across all predefined subgroups ‡
KRd(n=396)
Rd(n=396)
HR; P value
Median PFS, months 26.3 17.6 HR = 0.69; P=0.0001*
Median OS, months2-year OS, %
NR73.3
NR65.0
HR = 0.79; P=0.04†
Time to response, months 1.0 1.0 ─
Median DOR, months 28.6 21.2 NR
*Prespecified stopping boundary was met† Interim analysis, prespecified stopping boundary was not met‡ Predefined subgroups included sex, age, geographic region, β2M level, cytogenetics,
peripheral neuropathy at baseline, prior BORT, prior LEN, any prior IMiD, nonresponsive to BORT in prior regimen, refractory to prior IMiD Stewart AK et al. N Engl J Med. 2015;372:142.
51
ASPIRE: KRd vs RdProgression-Free Survival
Figure 1, page 148
Stewart AK et al. N Engl J Med. 2015;372:142.
Rd (n = 325)LEN: 25 mg, d1–21DEX: 40 mg, d1, 8, 15, 2228-day cycles until progression
N=646RRMM
1–3 prior linesNot LEN-refractory
ERd (n = 321)ELO: 10 mg/kg, d1, 8, 15, 22 IV(cycles 1–2); d1, 15 (cycles ≥ 3);LEN: 25 mg, d1–21DEX: weekly equivalent, 40 mg
28-day cycles until progression
• Primary end points: PFS, ORR• Secondary end points: OS, DoR, QoL, safety
ELOQUENT 2: Elotuzumab-Rd (ERd) vs Rd
Lonial S et al. N Engl J Med. 2015;373:621.
52
CRVGPRPR
ELOQUENT-2: ERd vs RdEfficacy
*Values may not sum due to rounding.
46 38
2821
4
7
0
20
40
60
80
100
ERd Rd
Pat
ien
ts (
%)
ORR 79%a
ORR 66%*
n=321 n=325
P<0.001 ERd(n=321)
Rd(n=325)
HR; P value
Median PFS, months2 19.4 14.9 0.73;
0.0014
Median TTNT, months2 33 21
0.62(95% CI
0.50–0.77)
Median OS, months2 43.7 39.6 0.77;
0.0257
Median DoR, months1 20.7 16.7 NR
Responses1
1. Lonial S et al. N Engl J Med. 2015;373:621-31.2. Dimopoulos MA et al. Blood. 2015;126: Abstract 28.
ELOQUENT-2: ERd vs RdProgression-Free Survival
Dimopoulos MA et al. Blood. 2015;126: Abstract 28.
ERd(n=321)
Rd(n=325)
Median PFS, mos (95% CI)
19.4 (16.6−22.2) 14.9 (12.1−17.2)HR=0.73 (95% CI 0.60−0.89; P=0.0014)
3-yr PFS, % 26 18
Figure 1, page 627
Lonial S et al. N Engl J Med. 2015;373:621.
53
FOLLOW-UP Every 4 weeks until PD, then every 12
weeks for OS
TOURMALINE-MM1: Ixazomib-Lenalidomide-Dexamethasone vs Lenalidomide-Dexamethasone
• Primary end point: PFS by independent review committee using IMWG criteria• Key secondary end points: OS, OS in high-risk patients† with del(17)
*10 mg for pts with CrCl ≤ 60 or ≤ 50 mL/min, depending on local practice/label.†High-risk was defined as del(17p), t(4;14), or t(l4;16), including 10% del(17p).
IRdLEN: 25 mg* PO d1–21DEX: 40 mg PO d1, 8, 15, 22IXA: 4 mg PO d1, 8, 1528-day cycles
Rd + PlaceboLEN: 25 mg* PO d1–21DEX: 40 mg PO d1, 8, 15, 22Placebo: PO d1, 8, 1528-day cycles
1:1
Stratification:• Prior treatment • ISS stage • PI exposure
Moreau P et al. N Engl J Med. 2016;374:1621.
N=722Pts with RRMM
1–3 prior therapiesNot LEN- or PI-refractory
30 33
36 32
12 7
0
20
40
60
80
100
IRd Rd
Pat
ien
ts (
%)
TOURMALINE-MM1: IRd vs RdEfficacy Summary
n=360 n=362
P<0.001
Responses
*Values may not sum due to rounding.
ORR 78%*ORR 72%a
CRVGPRPR
CR: P=0.019;CR + VGPR: P=0.014
Moreau P et al. N Engl J Med. 2016;374:1621.
Table 2, page 1626
Moreau P et al. N Engl J Med. 016;374:1621.
54
• Consistent PFS benefit across pre-specified patient subgroups
TOURMALINE-MM1: IRd vs RdPFS Analysis
Figure 1, page 1627
Moreau P et al. N Engl J Med. 2016;374:1621.
ENDEAVOR Study Design
Dimopoulos MA et al. Lancet Oncol. 2016;17:27.
KdCarfilzomib 56 mg/m2 IV
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 Days 1, 2, cycle 1 only)Infusion duration: 30 minutes for all doses
Dexamethasone 20 mg Days 1, 2, 8, 9, 15, 16, 22, 23
28-day cycles until disease progression or unacceptable toxicity
VdBortezomib 1.3 mg/m2 (3–5 second IV bolus or subcutaneous injection)
Days 1, 4, 8, 11Dexamethasone 20 mg
Days 1, 2, 4, 5, 8, 9, 11, 1221-day cycles until disease progression or unacceptable toxicity
BOR NAÏVE OR BOR SENSITIVE
Randomization 1:1 N=929
Stratification:• Prior proteasome
inhibitor therapy• Prior lines of
treatment• ISS stage• Route of
administration
• Primary end point: PFS
55
ENDEAVOR: Kd vs Vd in RRMMProgression-Free Survival
• Median follow-up: 11.9 mos for Kd; 11.1 mos for Vd Kd(n=464)
Vd(n=465)
Median PFS, months(95% CI)
18.7(15.6−NE)
9.4(8.4−0.4)
Hazard ratioP value
0.53 (0.44−0.65)<0.0001
Dimopoulos MA et al. Lancet Oncol. 2016;17:27.
*Predefined subgroups included sex, age, geographic region, ECOG performance status baseline creatinine clearance, previous peripheral neuropathy, disease stage, cytogenetics, number of prior regimens, prior transplant, prior BORT, prior IMiD, prior LEN, prior THAL, refractory to prior BORT, refractory to prior LEN.
• A consistent PFS benefit for Kd was observed across predefined subgroups
PF
S (
%)
0
20
40
60
80
100
0 6 12 18 24 30Time (years)
Kd
Vd
PANORAMA 1: Panobinostat + Bortezomib and Dexamethasone vs Bortezomib and Dexamethasone
• Multicenter, randomized, double-blind, placebo-controlled, phase 3 study
Study population
• N = 768
• 1–3 lines prior therapy
• Measurable M protein component in serum or urine at study screening
• ECOG ≤2
Treatment phase 1 (TP1) Treatment phase 2 (TP2)
PanVD (42-day cycle)Panobinostat• 20 mg PO as TP1 + on d22, 24, 26, 29, 31, 33Bortezomib• 1.3 mg/m2 IV d1, 8, 22, 29Dexamethasone• 20 mg PO on d1, 2, 8, 9, 22, 23, 29, 30
Placebo + VD (42-day cycle)PlaceboBortezomib• As aboveDexamethasone• As above
R
• Primary end point: PFSSan Miguel JF et al. Lancet Oncol. 2014;15:1195.
Placebo + VD (21-day cycle)PlaceboBortezomib• As aboveDexamethasone• As above
PanVD (21-day cycle)Panobinostat• 20 mg PO on d1, 3, 5, 8, 10, 12Bortezomib• 1.3 mg/m2 IV on d1, 4, 8, 11Dexamethasone• 20 mg PO on d1, 2, 4, 5, 8, 9, 11, 12
56
PanoVD for RRMM Patients Who Received Prior Bortezomib and IMiDs
• Subgroup analysis of patients who received ≥2 previous treatments, including bortezomib and an IMiD indication based on subgroup analysis
San-Miguel JF et al. J Clin Oncol. 2015;33: Abstract 8526.Richardson PG et al. Blood. 2016;127:713.
Figure 1, page 716
Richardson PG et al. Blood. 2016;127:713.
MM-003 NIMBUS: Pomalidomide Dexamethasone vs Dexamethasone
*Thromboprophylaxis was indicated for those receiving POM or with deep vein thrombosis history. San Miguel JF et al. Lancet Oncol 2013;14:1055.
(n=302)POM*: 4 mg/day Day 1–21 +LoDEX: 40 mg (≤75 years)
20 mg (>75 years)Day 1, 8, 15, 22
RA
ND
OM
IZA
TIO
N 2
:1(N
=45
5)
Follow-up for OS and SPM until
5 years post-enrollment
(n=153)HiDEX: 40 mg (≤75 years)
20 mg (>75 years) Day 1–4, 9–12, 17–20
28-day cycles
PD
PD Companion trialMM-003C
POM 21/28 days
Stratification• Age (≤75 vs >75 yrs)• Number of prior treatments (2 vs >2)• Disease population (primary refractory vs relapsed/refractory vs intolerance/failure)
• Primary end point: PFS
57
MM-003 NIMBUS: POM + LoDEX vs HiDEX PFSMedian Follow-Up 15.4 months
Adapted from Figure 2, page 1059
San Miguel JF et al. Lancet Oncol 2013;14:1055.
Myeloma X: Autologous Transplantation vs Ongoing Chemotherapy
Bortezomib, doxorubicin, dexamethasone (PAD)
Response ≥SD
PBSC mobilization
Follow-up
RR
PDor
CD34+ cells <2×106/kg
Off study
Cook G et al. Lancet Oncol. 2014;15:874.
N=297
N=89 N=89
Melphalan 200mg/m2 IVASCT
Cyclophosphamide 400 mg/m2 PO/week × 12
58
Myeloma X: Autologous Transplantation vs Ongoing Chemotherapy PFS
Figure 2, page 879
Cook G et al. Lancet Oncol. 2014;15:874.
ASPIRE: Carfilzomib (KRd vs Rd)Safety Profile
• 15% of patients in the KRd group and 18% in the Rd group discontinued treatment due to AEs• 8% of patients in the KRd group and 9% in the Rd group died while on treatment or within 30 days of last dose
Table 3, page 151
Stewart AK et al. N Engl J Med.2015;372:142.
59
ENDEAVOR: Carfilzomib (Kd vs Vd)Cardiac Substudy
All grades
Cardiac Substudy Overall Safety Population
Kd (N=74)n (%)
Vd (N=74)n (%)
Kd (N=463)n (%)
Vd (N=456)n (%)
Cardiac arrhythmias (SMQN) 3 (4.1) 3 (4.1) 29 (6.2) 43 (9.4)
Cardiac failure (SMQN) 8 (10.8) 3 (4.1) 38 (8.2) 13 (2.9)
Decreased ejection fraction 4 (5.4) 2 (2.7) 10 (2.2) 4 (0.9)
Cardiac failure 3 (4.1) 1 (1.4) 15 (3.2) 4 (0.9)
Cardiac failure acute 1 (1.4) 0 4 (0.9) 1 (0.2)
Cardiac failure chronic 1 (1.4) 0 1 (0.2) 0
Right ventricular failure 0 1 (1.4) 1 (0.2) 1 (0.2)
Ischemic heart disease (SMQN) 0 2 (2.7) 13 (2.8) 9 (2.0)
Respiratory, thoracic, and mediastinal disorders 31 (41.9) 25 (33.8) 264 (57.0) 161 (35.3)
Hypertension 15 (20.3) 6 (8.1) 115 (24.8) 40 (8.8)
Dimopoulos MA et al. Lancet Oncol. 2016;17:27.
ELOQUENT-2: Elotuzumab (ERd vs Rd) Safety Profile
Lonial S et al. N Engl J Med. 2015;373:621.
Table 3, page 630
Lonial S et al. N Engl J Med. 2015;373:621.
60
TOURMALINE-MM1: IRd vs Rd Safety Profile
Table 4, page 1630
Moreau P et al. N Engl J Med. 2016;374:1621.
MM03 NIMBUS Pom Dex vs Dex Safety Profile
Table 4, page 1630
San Miguel JF et al. Lancet Oncol2013;14:1055.
61
Conclusions• Many choices
– Good response, improved PFS, good safety profiles
• Individualize the choice toward the specific patient– Type of relapse– Previous therapy received– Previous side effects– Oral vs IV
• Aim for a triplet• Monitor closely and manage side effects
– Staying on treatment is the key
The Way Forward: Immunotherapy
Paul G. Richardson, MDR.J. Corman Professor of Medicine
Harvard Medical SchoolClinical Program Leader and Director of Clinical Research
Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute
Boston, Massachusetts
62
Key Targets in MM• Excess protein production
>> Target protein degradation
• Genomic abnormalities and acquired resistance
>> Target and overcome mutations
• Immune suppression
>> Restore anti-MM immunity
WGS at Diagnosis
Courtesy of Nikhil Munshi MD, DFCI
63
Courtesy of Nikhil Munshi MD, DFCI
WGS at Relapse
Restoring Immune Function• Immunomodulatory drugs, other small
molecules (eg, HDACi’s)
• Monoclonal antibodies
• Checkpoint inhibitors
• Vaccines
• Cellular therapies
64
MM cells
Bone marrow stromal cells
Dendritic cells
IL-6
TNFα
IL-1βA
IL-2
IFN
CD8+ T cells
C
E
Bone marrow vessels
ICAM-1
VEGFbFGF
D
B
NK cellsNK-T cells
PKCNFAT
PI3K
IL-2
CD28
Lenalidomide and Pomalidomide in MM
Hideshima T et al. Blood. 2000;96:2943.Davies FE et al. Blood. 2001;98:210.Gupta D et al. Leukemia. 2001;15:1950.Mitsiades N et al. Blood. 2002;99:4525.
Lentzsch S et al. Cancer Res. 2002;62:2300.LeBlanc R et al. Blood. 2004;103:1787.
Hayashi T et al. Br J Haematol. 2005;128:192.
Immunomodulatory AgentsIMiDs: Mechanism of Action
Krönke J et al Science. 2014;343:301. Lu G et al. Science 2014;343:305.
Adapted from Figure, page 347
Stewart AK. Science. 2014;343:256.
65
Model of Lenalidomide and Pomalidomide Costimulationof T Cells via Degradation of Aiolos and Ikaros
Figure 9, page 819
Gandhi AK et al. Br J Haematol. 2014;164:811.
3 1 7
30 24
12 8
0
10
20
30
40
50
MM 002 MM 003
MRPRVGPRCR/sCR
Efficacy Results of POMALIDOMIDE + LoDEX in Advanced RRMM (Phase 2/3: MM002 & MM003)
ORR = 33% ORR = 32%
Per
cen
tag
e R
esp
on
se
MM-002 (n=113)1MM-0021 MM-0032,3
Median follow-up, months 14.2 15.4
Median DoR, months 8.3 7.5
Median PFS, months 4.2 4.0
Median OS, months 16.5 13.1
1. Richardson PG et al. Blood. 2014;123:1826.2. San Miguel J et al. Lancet Oncology. 2013;14:1055.
3. San Miguel J et al. Blood. 2013;122; Abstract 686.
MM-002 (n=113)1 MM-003 (n=302)2,3
66
Monoclonal Antibodies Kill MM Through Multiple Mechanisms
DIRECT EFFECTS INDIRECT EFFECTSInterferes with
survival ordelivers myeloma-killing substances
Labels myeloma cells for killing by complement
Labels myeloma cells for killing by NK cells
Monoclonal antibody
Myeloma cell surface target
Complement
Fc receptor
NK cell toxins
Activates T cells by taking the brakes off
Checkpoint inhibitor
Adapted from Richardson PG, ASH 2012
• Elotuzumab is an immunostimulatory monoclonal antibody that recognizes SLAMF7, a protein highly expressed by myeloma and natural killer cells1
• Elotuzumab causes myeloma cell death via a dual mechanism of action2
1. Hsi ED et al. Clin Cancer Res. 2008;14:2775.2. Collins SM et al. Cancer Immunol Immunother. 2013;62:1841.
Directly activating natural killer cells
A
Tagging for recognition (ADCC)
B
EAT-2
Perforin,granzyme Brelease
ElotuzumabNatural killer cell
SLAMF7
Myeloma cellMyelomacell
DegranulationDownstreamactivating signalingcascade
EAT-2SLAMF7
Polarization
Natural killer cell
Granule synthesis
Myelomacell death
Elotuzumab: Immunostimulatory Mechanism of Action
67
ELOQUENT-2: Primary Analysis
1. Lonial S et al. N Engl J Med. 2015;373:621.
ELOQUENT-2 demonstrated clinical benefits of E-Ld
compared with lenalidomide and dexamethasone (Ld)
alone1
ELOQUENT-2 demonstrated clinical benefits of E-Ld
compared with lenalidomide and dexamethasone (Ld)
alone1
Figure 1, page 627
Lonial S et al. N Engl J Med.2015;373:621.
From Table 2, page 629
Lonial S et al. N Engl J Med.2015;373:621.
1.0
0.8
0.6
0.4
0.2
0.0
Pro
ba
bil
ity
Pro
gre
ss
ion
Fre
e 0.9
0.7
0.5
0.3
0.1
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
PFS (months)
Elotuzumab in High-Risk Patients
Lonial S et al. J Clin Oncol. 2015;33. Abstract 8508.
ELOQUENT-2 Study ResultsProgression-Free Survival of Patients With del(17p) and t(4;14) Translocation
1.0
0.8
0.6
0.4
0.2
0.0
Pro
ba
bil
ity
Pro
gre
ss
ion
Fre
e 0.9
0.7
0.5
0.3
0.1
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
PFS (months)
t(4;14)+del(17p)+
Hazard ratio: 0.65(95% CI, 0.450.94)
Hazard ratio: 0.53(95% CI, 0.290.95)
E-Ld
Ld E-Ld
Ld
68
Daratumumab: Mechanism of Action• Human CD38 IgGκ
monoclonal antibody • Direct and indirect anti-
myeloma activity1-5
• Depletes CD38+ immunosuppressive regulatory cells5
• Promotes T-cell expansion and activation5
1. Lammerts van Bueren J et al. Blood. 2014;124: Abstract 3474. 2. Jansen JHM et al. Blood. 2012;120: Abstract 2974.3. de Weers M et al. J Immunol. 2011;186:1840. 4. Overdijk MB et al. MAbs. 2015;7:311.
5. Krejcik J et al. Blood. 2016;128:384.
Lokhorst HM et al. N Engl J Med. 2015;373:1207. Lonial S et al. Lancet. 2016;387:1551.
69
Daratumumab Monotherapy: Efficacy in Combined Analysis
Usmani SZ et al. Blood. 2016;128:37.
Figure 4, page 42
Usmani SZ et al. Blood. 2016;128:37.
20
35
5
OR
R, %
10
25
15
0
Lonial S et al. Lancet. 2016;387:1551.
40
30
Daratumumab Phase 2 StudySingle Agent in RRMM
33 3330
21 20
30 29 28 28 2621
ORR by Subgroup
Refractory to
70
Daratumumab Phase 2 StudySingle Agent in RRMM
Progression-Free and Overall Survival
20
80
Pat
ien
ts
Pro
gre
ssio
n-F
ree
and
Aliv
e (%
)
40
0
100
60
0 2 4 6 8 10 12 14 16Months From Start of Treatment
Median PFS = 3.7 months(95% CI, 2.8–4.6)
• 29 of 31 responders are still alive• 1-year survival rate 65% (95% CI, 51.2–75.5)
Lonial S et al. Lancet. 2016;387:1551.
Figure 4, page 1558
Lonial S et al. Lancet. 2016;387:1551.
Synergistic With Other Standard MM Therapies, Including Bortezomib and Lenalidomide
Modified from Figure 1, page e42
van der Veer MS et al. Blood Cancer J.2011;1:e41.
71
Palumbo A et al. N Engl J Med. 2016;375:754.
Phase 3 Randomized Controlled Study of DVd vs Vd in Pts With Relapsed or Refractory MM: CASTOR
CASTOR Study DesignMulticenter, randomized, open-label, active-controlled phase 3 study
Key eligibility criteria
• RRMM
• ≥1 prior line of therapy
• Prior bortezomib exposure, but not refractory
Primary end point• PFSSecondary end point• TTP• OS• ORR, VGPR, CR• MRD• Time to response• Duration of response
RANDOMIZE
DVd (n=251)Daratumumab (16 mg/kg IV)Every week: cycles 1–3Every 3 weeks: cycles 4–8Every 4 weeks: cycles 9+Vel: 1.3 mg/m2 SC, days 1, 4, 8, 11: cycles 1–8Dex: 20 mg PO-IV, days 1, 2, 4, 5, 8, 9, 11, 12: cycles 1–8
Vd (n=247)Vel: 1.3 mg/m2 SC, days 1, 4, 8, 11: cycles 1–8Dex: 20 mg PO-IV, days 1, 2, 4, 5, 8, 9, 11, 12: cycles 1–8
1:1
• Cycles 1–8: repeat every 21 days• Cycles 9+: repeat every 28 days
Statistical analyses• 295 PFS events: 85%
power for 4.3 month PFS• Interim analysis: ~177
PFS eventsDaratumumab IV administered in 1,000 mL to 500 mL;
gradual escalation from 50 mL to 200 mL/hour permitted
Palumbo A et al. N Engl J Med. 2016;375:754.
72
Phase 3 Randomized Controlled Study of DVd vs Vd in Pts With Relapsed or Refractory MM: CASTOR
CASTOR Efficacy
DVd Vd HR 95% CI P Value
N 251 247 ─ ─ ─
PFS (mos) NR 7.2 0.39 0.280.53 <0.0001
1-year PFS (%) 60.7 26.9
Median TTP (mos) NR 7.3 0.30 0.210.43 <0.0001
ORR (%) 83 63 ─ ─ <0.0001
≥VGPR 59 29 ─ ─ <0.0001
≥CR 19 9 ─ ─ 0.0012
MRD-negative (10-4) (%) 14 3 ─ ─
Median duration of response (mos) NR 7.9 ─ ─ ─
Palumbo A et al. N Engl J Med. 2016;375:754.
Phase 3 Randomized Controlled Study of DVd vs Vdin Pts With Relapsed or Refractory MM: CASTOR
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15
DVd
Vd26.9%
60.7%
1-year PFS*Median: not reached
Median: 7.2 months
HR: 0.39 (95% CI, 0.28-0.53); P<0.0001Pro
po
rtio
n S
urv
ivin
g
Wit
ho
ut
Pro
gre
ssio
n
61% reduction in the risk of disease progression or death for DVd vs Vd
No. at riskVd 247 182 106 25 5 0
DVd 251 215 145 56 11 0
CASTOR PFS
Palumbo A et al. N Engl J Med. 2016;375:754.
73
Daratumumab + Lenalidomide + Dexamethasone: Overall Response Rate
• ORR = 81%• Clinical benefit rate (ORR + minimal response) = 88%
From Table 4, page 1825
Plesner T et al. Blood. 2016;128:1821.
Dimopoulos M et al. N Engl J Med. 2016;375:1319.
74
Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX
POLLUX Study DesignKey eligibility
criteria• RRMM• ≥1 prior line of
therapy• Prior lenalidomide
exposure, but not refractory
• Patients with creatinine clearance ≥30 mL/min
Primary end point• PFS
Secondary end point• TTP• OS• ORR, VGPR, CR• MRD• Time to response• Duration of response
RANDOMIZE
DRd (n=286)Daratumumab 16 mg/kg V• Qw in Cycles 1–2, q2w in Cycles 3–6, then q4w until
PD
R 25 mg PO• Days 1–21 of each cycle until PD
d 40 mg PO• 40 mg weekly until PD
Rd (n=283)R 25 mg PO• Days 1–21 of each cycle until PD
d 40 mg PO• 40 mg weekly until PD
1:1
Cycles: 28 days
Statistical analyses• 295 PFS events: 85%
power for 7.7 month PFS improvement
• Interim analysis: ~177 PFS eventsPre-medication for the DRd treatment group consisted of
dexamethasone 20 mga, paracetamol, and an antihistamine.
Stratification factors• No prior lines of therapy• ISS stage at study entry• Prior lenalidomide
Dimopoulos M et al. N Engl J Med. 2016;375:1319.
POLLUX PFS
Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15
Pro
po
rtio
n S
urv
ivin
gW
ith
ou
t P
rog
ress
ion
No. at riskRd 283 249 206 179 139 36 5 0
DRd 286 266 248 232 189 55 8 0
63% reduction in the risk of disease progression or death for DRd vs Rd
18 24
DRd78%
18-month PFS*12-month PFS*
Median PFS: 18.4 months
HR: 0.37 (95% CI, 0.27–0.52); P<0.0001
83%
Rd
60%52%
Dimopoulos M et al. N Engl J Med. 2016;375:1319.
75
Phase 3 Randomized Controlled Study of DRd vs Rdin Pts With Relapsed or Refractory MM: POLLUX
POLLUX Efficacy
DRd Rd P Value
N 286 283 ─
ORR (%) 93 76 <0.0001
≥VGPR 76 44 <0.0001
≥CR 43 19 <0.0001
Median duration of response (mos)
NR 17.4 ─
Dimopoulos M et al. N Engl J Med. 2016;375:1319.
Phase 3 Randomized Controlled Study of DRd vs Rdin Pts With Relapsed or Refractory MM: POLLUX
POLLUX MRD-Negativity Rate50
40
30
20
10
0
MR
D-n
egat
ive
Rat
e (%
)
MRD-neg (10-4) MRD-neg (10-5) MRD-neg (10-6)
45
35
25
15
5
30%
8%
23%
5%
10%
2%
P<0.0001
P<0.0001
P<0.0001
DRdRd
Dimopoulos M et al. N Engl J Med. 2016;375:1319.
76
20
35
5
OR
R, %
10
25
15
0
Lonial S et al. J Clin Oncol. 2015;33. Abstract LBA 8512.
40
30
Daratumumab in High-Risk Patients
33 3330
21 20
30 29 28 28 2621
Daratumumab Phase 2 StudySingle Agent in RRMM ORR by Subgroup
Refractory to
Updated Data From a Dose Finding Phase II Trial of Single Agent Isatuximab (Anti-CD38 mAb)
in Relapsed/Refractory Multiple Myeloma [ASCO 2016]
Joshua Richter,1 Thomas Martin,2 Ravi Vij,3 Craig Cole,4 Djordje Atanackovic,5 Jeffrey Zonder,6Jonathan Kaufman,7 Joseph Mikhael,8 William Bensinger,9 Meletios Dimopoulos,10 Todd
Zimmerman,11 Nikoletta Lendvai,12 Parameswaran Hari,13 Enrique Ocio,14 Cristina Gasparetto,15
Shaji Kumar,16 Corina Oprea,17 Eric Charpentier,17 Stephen Strickland,18 Jesús San Miguel19
1Hackensack University Medical Center, Hackensack, NJ, USA; 2University of California at San Francisco, San Francisco, CA, USA; 3Washington University, St. Louis, MO, USA; 4University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA; 5Huntsman Cancer Institute, Salt Lake City, UT, USA; 6Karmanos Cancer Center,
Detroit, MI, USA; 7Winship Cancer Institute of Emory University, Atlanta, GA, USA; 8Mayo Clinic, Scottsdale, AZ, USA; 9Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 10National and Kapodistrian University of Athens, Athens, Greece; 11University of Chicago, Chicago, IL, USA; 12Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 13Medical College of Wisconsin, Milwaukee, WI, USA; 14University Hospital of Salamanca, Salamanca, Spain; 15Duke University Medical
Center, Durham, NC, USA; 16Mayo Clinic, Rochester, MN, USA; 17Sanofi-Genzyme Oncology, Cambridge, MA, USA; 18Vanderbilt-Ingram Cancer Center, Nashville, TN,19University of Navarra, Pamplona, Spain
Isatuximab
CD38
77
ASCO 2016: Summary• Isatuximab was generally well tolerated at ≥10 mg/kg
– Most infusion reactions were grade 1/2, and occurred during the first infusion
– Median infusion duration is shorter following the first infusion• Isatuximab demonstrated single-agent activity in heavily pretreated patients
with RRMM– Median 5 (2–14) prior lines of therapy
• The ORR was 20%–29% at isatuximab ≥10 mg/kg– ORR was similar across subgroups, including high-risk cytogenetics– Median duration of response was 8.75–12.9 (3.7–14.8) months
• At isatuximab ≥10 mg/kg, PFS was 3.65 months and OS was 18.63 months– 11 patients remained on treatment at data cutoff– Median OS has not been reached in the 20 mg/kg QW/Q2W and 10 mg/kg
Q2W/Q4W cohortsRichter JR et al. J Clin Oncol. 2016;34: Abstract 8005.
NK B
NKT
CD4
CD8
pDC, MDSC induced immune suppression
MMMM MM
Stroma
IL-6, IL-10, TGFβ, PGE, ARG1, NO, ROS, COX2
Depletion of cysteine
MM induced immune
suppression
Tumor promotion and induction of PD-L1
expression
MMPD-L1
Treg
PD-L1
TAMPD-L1
MDSCPD-L1
PD1PD1
pDC
Görgün GT et al. Blood. 2013;121:2975.
Immune Suppressive Microenvironment in MM
PD1
PD1PD1
78
Target PD-1, PDL-1
Allow T cells to function
Current agents under investigation in MM: nivolumab and pembrolizumab
Activity only in combination with other MM agents
Immune Checkpoint Inhibitors in MM
Immune Checkpoint Inhibitors for Relapsed/Refractory Multiple Myeloma
Keynote-023: Pembrolizumab + Lenalidomide and Dexamethasone1
Phase 2 of Pembrolizumab + Pomalidomide and Dexamethasone2
Patient populationRRMM for whom ≥2 prior therapies, including a proteasome inhibitor and an IMiD, have failed
RRMM for whom ≥2 prior therapies, including a proteasome inhibitor and an IMiD, have failed
Dosing
Pembrolizumab 200 mg fixed dose* 200 mg IV every 2 weeks
IMiD Lenalidomide: 25 mg Pomalidomide: 4 mg daily 21 days
Dexamethasone 40 mg (low-dose) 40 mg weekly
Response 17 patients; 76% response rate 11 of 22 evaluable patients (50% response rate)
*Used in the phase 2 portion of study based on MTD/MAD
1. San Miguel J et al. Blood. 2015;126: Abstract 505.2. Badros AZ et al. Blood. 2015;126: Abstract 506.
79
Durvalumab
Figure 1, page 475
Ibrahim R et al. Semin Oncol. 2015;42(3):474.
Harnessing the Immune System to Fight Myeloma
Passive Active
Monoclonal antibodies
Chimeric antigen receptor (CAR) T cells
Vaccines (therapeutic not preventive)
Types of Immunotherapy, Immuno-Oncology
Direct effects
CDC
Cell death
ADCC
NK cell
Myeloma cellFc receptor
LysisMAC
C1q
Antigen
Monoclonal antibody
3. Infuse MM-targeted cells back to
patient
2. Modify andexpand cells
in lab
1. Extract WBCsfrom patient
80
Phase 1 Trial of Vaccination With DC/MM Fusions in RRMM
• Well tolerated, no autoimmunity
• Induced tumor reactive lymphocytes in a majority of patients
• Induced humoral responses to novel antigens (SEREX analysis)
• Disease stabilization in 70% of patients
• DC/MM fusions induce anti-MM immunity in vitro and inhibit MM cell growth in vivo in xenograftmodels
Rosenblatt J et al. Blood. 2011;117:393.Vasir B et al. Br J Haematol. 2005;129:687.
Figure 1, page 396
Rosenblatt J et al. Blood.2011;117:393.
• Goal is to prevent evolution of smoldering to active myeloma
• Cocktails of immunogenic HLA-A2-specific XBP1, CD138, CS1 peptides to induce MM-specific and HLA-restricted CTL responses
• Clinical trials: – Immune responses to vaccine in all patients – Lenalidomide with vaccine to augment immune response– Lenalidomide and PDL-1 with vaccine to induce memory– Immune response against myeloma Bae J et al. Leukemia. 2011;25:1610.
Bae J et al. Br J Haematol. 2011;155:349.Bae J et al. Br J Haematol. 2012;157:687.Bae J et al. Clin Can Res. 2012;17:4850.
Bae J et al. Leukemia. 2015;29:218.
Vaccines Targeting MM-Specific Peptides in Smoldering MM
81
Therapeutic Vaccines in Development
MM Vaccine Patient TypesStudyPhase Sites
Dendritic cell fusion vaccine + CT-011 (monoclonal antibody) Post-transplant* 2 Beth Israel Deaconess Medical Center/
Dana-Farber
Hiltonol (MAGE-A3 vaccine Poly-ICLC) Post-transplant* 2 University of Pennsylvania
Oncolytic measles virus (MV-NIS) RR 1 Mayo Clinic (Rochester, MN)
Oncolytic measles virus (MV-NIS) RR 2 University of Arkansas
PVX-410 SMM 1/2
Emory/Illinois Cancer Specialists/Beth Israel Deaconess Medical Center/Massachusetts General Hospital/ DFCI/ MD Anderson Cancer Center
PVX-410 Post-transplant 2 Emory University
*Goal of eliminating any remaining cancer cells
Immune Cell Therapy in DevelopmentType Trial Patient Types
StudyPhase Site(s)
CAR T
CART-19 for multiple myeloma Relapsed/ refractory 1 University of Pennsylvania
Safety study of CAR-modified T cells targeting NKG2D-ligands Relapsed/ refractory 1 Dana-Farber Cancer Institute
Study of T cells targeting B-cell maturation antigen (BCMA) for previously treated multiple myeloma Relapsed/ refractory 1 National Cancer Institute
University of Pennsylvania
MILs
Tadalafil and lenalidomide maintenance with or without activated marrow infiltrating lymphocytes (MILs) in high-risk myeloma
Newly diagnosed; relapsed (without prior ASCT)
2 Sidney Kimmel Comprehensive Cancer Center
Adoptive immunotherapy with activated marrow-infiltrating lymphocytes and cyclophosphamide graft-versus-host disease prophylaxis in patients with relapse of hematologic malignancies after allogeneic hematopoietic cell transplantation
Relapsed/ refractory 1 Sidney Kimmel Comprehensive Cancer Center
Affinity-enhanced T cells
Engineered autologous T cells expressing an affinity-enhanced TCR specific for NY-ESO-1 and LAGE-1
Relapsed/refractory 1/2 City of Hope
University of Maryland
DLI CD3/CD28 activated Id-KLH primed autologous lymphocytes Post-transplant 2 University of Pennsylvania
82
Myeloma CAR Therapy• Multiple promising targets:
– CD19, CD138, CD38, CD56, kappa, Lewis Y, CD44v6, CS1 (SLAMF7), BCMA
• Functional CAR T cells can be generated from MM patients• CAR T and NK cells have in vitro and in vivo activity against MM• Clinical trials under way
– Anecdotal prolonged responses but no robust efficacy data available yet
• Many questions remain about CAR design:– Optimal costimulatory domains– Optimal vector– Optimal dose and schedule– Need for chemotherapy– Perhaps “cocktails” of multiple CARs or CARs + chemotherapy will be
required for best outcomes
MM Pt #1: Response to CD19 CAR Therapy
Figures 1 and 2, page 1042
Garfall AL et al. N Engl J Med. 2015;373:1040.
83
First-in-human phase 1 trial
• CAR-BCMA expression determined by flow cytometry
CAR-BCMA T Cells in MM: Study Design
Pts with advanced RRMM; ≥3 prior lines of therapy; normal organ function;
clear, uniform BCMA expression on MM cells
(N=12)
CAR-BCMA T cells*Single infusion
Cyclophosphamide 300 mg/m2
Fludarabine 30 mg/m2
QD for 3 days
*Dose escalation of CAR+ T cells/kg
0.3 × 106
1.0 × 106
3.0 × 106
9.0 × 106
Ali SA et al. Blood. 2016;128:1688.
CAR-BCMA T Cells in MM: Response
Table 1, page 1690
Ali SA et al. Blood. 2016;128:1688.
84
Bi-Specific Antibody (bsAb) Constructs
~
BivalentAntibody
conjugates TetravalentSmall molecules
(eg, BiTEs)
Derived from Kontermann RE, Brinkmann U. Drug Discov Today. 2015;20:838.Zonder J. Presented at: 15th International Myeloma Workshop . Rome, Italy. September 2015.
Integration and Impact of Novel Agents, including Immune Therapies
• Innovations (PIs, IMiDs) to date have produced significant improvements in PFS and OS: recent approvals (eg, carfilzomib, ixazomib) will augment this
• Next wave of therapies…crucially, agnostic to mutational thrust?
• Baseline immune function appears to also be a key barrier to success but may be targetable (eg, use of PD1/PDL1 blockade)
• MoAbs (Elo, DARA, ISA) have activity in high-risk disease and represent true new novel mechanisms, as well as other immuno-therapeutics (eg, checkpoint inhibitors, vaccines)
• New insights to mechanisms of drug action (eg, AC 241) are further expanding therapeutic opportunities with combinations
• Numerous other small molecule inhibitors show promise (eg, HDACis, CXCR4, BCL, AKT, CDK, HSP 90, Nuclear Transport, KSP, BET bromodomain proteins/Myc, DUBs, MEK)
• Further refinement of prognostics and MRD will guide therapy
85
Continuing Evolution of MM Treatment: Selected New Classes and Targets 2016
*Not yet FDA-approved for MM; available in clinical trials
1st-Generation Novel Agents 2nd-Generation Novel Therapies/Immunotherapy
Chemotherapy
Monoclonal antibody
Proteasome inhibitor
IMiD HDAC inhibitor
20122003 2006 2007 2013 2015
Carfilzomib
Bortezomib
Thalidomide
Lenalidomide
Pomalidomide
Panobinostat
Bortezomib + Doxil
2016+
Elotuzumab Isatuximab*
CAR-T*
Adoptive T cell therapy
Vaccines
Atezolizumab*Durvalumab*
Nivolumab*Pembrolizumab*
Checkpoint inhibitors
Vaccines*
Ixazomib
DaratumumabAC-241/1215*
Marizomib*
3rd Generation IMiDs*
Melflufen*
Academia
FDAEMEA
NIHNCI
AdvocacyMMRF/C;IMFIMWG; IMS
Pharmaceuticals
Progressand hope
19 new FDA-approved drugs/combos/indications in last 13 yrs
Ongoing MM Collaborative Model for Rapid Translation From Bench to Bedside
86