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 Genomics A. Keith Stewart, MBChB 8:40 AM – 8:55 AM Making Sense of Frontline Options Thierry Facon, MD 8:55 AM – 9:05 AM Community Case 2 Robert M. Rifkin, MD 9:05 AM – 9:20 AM Strategies to Prolong Response Amrita Y. Krishnan, MD 9:20 AM – 9:35 AM Panel Discussion 9:35 AM – 9:45 AM Community Case 3 Robert M. Rifkin, MD 9:45 AM – 10:00 AM New Agents, Classes in the Relapsed Setting Faith E. Davies MD 10:00 AM – 10:15 AM The Way Forward: Immunotherapy Paul G. Richardson, MD 10:15 AM – 10:30 AM Panel Discussion 10:30 AM – 11:00 AM Question and Answer Session
1 Patient Case 1
Robert M. Rifkin, MD Associate Chair – US Oncology Research Disease Lead – Multiple Myeloma Attending Physician Rocky Mountain Cancer Centers Denver, 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.
2 Case Study 1 75-year-old man referred for workup of back pain that radiated to ribs and chest. Past medical Past surgical Family Social Physical history history history history exam • Hypertension • Left rotator • Brother and • Married, • Normal •T2DM cuff repair 7 five sisters— bilingual • ROS: negative • Coronary years ago all healthy instructor for except for artery disease • Four children OSHA back pain with 2 stents • Nonsmoker, rare social alcohol • No substance use
Case Study 1: Labs
Actual Normal Actual Normal Value Range Value Range WBC (103/mL) 5.4 (4–11) IgG (mg/dL) 2,425 (H) (700–1,600) Quantitative Hemoglobin (g/dL) 12.0 (13–16) IgA (mg/dL) 20 (L) (70–400) CBC with Igs Hematocrit (%) 38 (34–45) differential IgM (mg/dL) 3 (L) (40–230) 3 Platelets (10 /mL) 210 (150–400) Kappa quant Free Lite Chain 112 (H) (3.30–19.40) Neutrophils (103/mL) 4.3 (1.9–7.5) (mg/L) BUN (mg/dL) 34 (7–20) FLC Lambda quant FLC (mg/L) 1.8 (L) (5.71–26.30) Creatinine (mg/dL) 1.5 (0.7–1.2) Kappa/lambda quant FLC 62.2 (H) (0.26–1.65) CMP Calcium (mg/dL) 9.4 (8.4–10.2) ratio Total protein (g/dL) 8.7 (6.3–8.2) Albumin (g/dL) 3.7 (3.5–5.0) β2M 4.5 SPEP + IF-IgG serum immuno- M protein spike (g/dL) 1.7 fixation
3 Case Study 1: Imaging and BM Biopsy
Bone BM Flow Cytogenetics imaging MRI biopsy cytometry and FISH
Skeletal survey • Multifocal lesions in • 70% cellular with • 25.6% events Cytogenetics • 1.6 cm lytic lesion spine and ribs 70%–80% plasma positive for CD38, • 46, XY CD56, CD138, and in the parietal bone; cells FISH (CD138 kappa light chain severe loss of bone • Aspirate 66% selected plasma mineralization— plasma cells cells) osteoporosis • 74% with gain of PET scan 1q21 • Expansile lytic • 5.4% low-level gain lesion in right of 11q23 acromion. Multiple • 91% with loss of areas of uptake in 13q14 bilateral ribs, and increased uptake in • 12.0 % with low- T5 level loss of TP53 • 92.5% positive for IgH rearrangement variant
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Advances in the Diagnostic Workup: Imaging and Genomics
A. Keith Stewart, MBChB, MRCP, FRCPC, MBA Carlson and Nelson Endowed Director Center for Individualized Medicine Vasek and Anna Maria Polak Professor of Cancer Research Consultant, Division of Hematology/Oncology, Mayo Clinic Rochester, Minnesota and Scottsdale, Arizona
4 Improving Survival in MM
1.0 1960–1965 0.9 25% of patients live 1965–1970 1970–1975 0.8 less than 3 years 1975–1980 0.7 1980–1985 0.6 1985–1990 1990–1995 0.5 1995–2000 0.4 2000–2005 2005–2010 0.3 Proportion Surviving 0.2 0.1 0.0 042681012141816 20 Follow Up From Diagnosis (Years) Adapted from Kumar SK et al. Leukemia. 2014;28:1122.
Prognostic Systems Combining Genetics and ISS Model
Table 2, page 3415: + Greipp PR et al. J Clin Oncol. 2005;23:3412.
Risk Criteria Median OS Lack of del(17p), Standard 50.5 mo t(4;14), t(14;16) At least one of 24.5 mo High del(17p), t(4;14) or (P<0.001) t(14;16)
Fonseca R et al. Leukemia. 2009;23:2210. Greipp PR et al. J Clin Oncol. 2005;23:3412.
5 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) 5-Year OS* 5-Year PFS* and/or t(14;16)] (%) (%) – Normal LDH level (less than the upper limit of R-ISS I 82 55 normal range) R-ISS II 62 36 • R-ISS III (n=295) R-ISS III 40 24 – Including ISS stage III (serum β2M level >5.5 *At a median follow-up of 46 months mg/L) – High-risk CA or high LDH level • R-ISS II (n=1,894) – Including all the other possible combinations
Palumbo A et al. J Clin Oncol. 2015;33:2863.
mSMART 2.0 Variable Outcomes in MM
High Intermediate Standard 20% 20% 60% • FISH • FISH t(4;14) • Others ‒ del 17p • Amplification ‒ Hyperdiploid ‒ t(14;16) chromosome 1q ‒ t(11;14) ‒ t(14;20) ‒ t(6;14) • GEP ‒ High-risk signature
3–4 years 5–6 years 8–10 years
Mikhael JR et al. Mayo Clin Proc. 2013;88:360.
6 Cytogenetics: Biologically Defined Unique Subsets
t(4;14)1 • Translocation upregulates MMSET + FGFR3 • Found in 15% of patients • Associated with IgA myeloma • Immature morphology Figure 2, page 2033 • Often associated with del17 • Tendency for less lytic bone disease, younger age Garand R et al. Leukemia. t(11:14)2 • Translocation upregulates cyclinD1 2003;17:2032. • 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.
Risk Stratification in Myeloma How 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
7 Venetoclax in t(11;14) MM
ORR by t(11;14) Status 50 sCR CR VGPR PR ORR 40% 200 40 3% Kappa FLC 150 7% 30 100 ORR 21% mg/dL 17% 20 3% 50 3% Generalized normal high
Percentage of of Patients Percentage 10 9% 0 ORR 6% Generalized normal low 13% 6% 3% 0 3% All Patients t(11;14) Non-t(11;14) or (n=6) (n=30) undetermined (n=36)
Kumar S et al. Blood. 2016;128: Abstract 488. A.K. Stewart, unpublished
Imaging in Myeloma: IMAJEM (NCT01309334)
ARM A Randomize ARM B
RVD × 3 PET-CT/MRI at diagnosis RVD × 3 PET-CT/MRI after 3 cycles CY (3g/m2) CY (3g/m2) MOBILIZATION MOBILIZATION Goal: 5 ×106 cells/kg Goal: 5 ×106 cells/kg
Melphalan 200 RVD × 5 mg/m2 + ASCT
RVD × 2 PET-CT/MRI before maintenance Lenalidomide 1 year Lenalidomide 1 year ASCT at relapse N=134 Moreau P et al. Blood. 2015;126: Abstract 395.
8 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.
9 PET-CT Normalization Before Maintenance Impact on PFS (62% Normalized)
1.0
0.8 69%
0.6 51.6% 0.4
P< 0.001 0.2
0.0 0 102030
Moreau P et al. Blood. 2015;126: Abstract 395.
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.
10 PET-CT Normalization Before Maintenance Impact on OS (62% Normalized)
1.0 94.6%
0.8 69.9%
0.6
0.4 P=0.003 0.2
0.0 0 10203040
Moreau P et al. Blood. 2015;126: Abstract 395.
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
11 Genomic Landscape in MM • >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.
Chapman MA et al. Nature. 2011;471:467. Walker BA et al. J Clin Oncol. 2015;33:3911. Bolli N et al. Nat Commun. 2014;5:2997. Lonial S et al. Blood. 2014;124: Abstract 722. Lohr JG et al. Cancer Cell. 2014;25:91. Keats JJ et al. Blood. 2012;120:1067.
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 Heme panel, 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.
12 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% 24% 92% 82% 94% TP53 78% 88%
Kortuem KM et al. Ann Hematol. 2015;94:1205.
13 Impact of Mutation on Myeloma Survival
Figure 3, page 3913 Walker BA et al. J Clin Oncol. 2015;33:3911.
Figure 4, page 3916 Walker BA et al. J Clin Oncol. 2015;33:3911.
Mutations in the Cereblon Pathway in at Least 26% of Relapsed/Refractory Patients
CRBN 1 CRBN * CUL4B 11 IMiDs IKZF3 111 DDB1 IRF4 11111 CUL4 * ROC1 • In a patient refractory to Len/Dex therapy we identified mutations in both IKZF1/3 * CRBN and IRF4 • One patient had 4 different CRBN mutations IRF4 • Probably higher as we did not look for MYC * structural change on chromosome 3 • 4 out of 5 IRF4-mutated patients shared MM cytotoxicity a K123R variant
*gene found mutated in cohort Kortüm KM et al. Blood. 2016;128:1226.
14 CoMMpass Enrollment • 1,000+ patients enrolled from >90 sites worldwide, with over 850 samples molecularly profiled at baseline and >100 sequentially
CoMMpass: Triplets versus Doublets Early 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)
15 CoMMpass: High Risk Disease Integrative 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 Options By looking closely at the molecular changes happening at progression, one can identify potential new therapeutic options (for ex. a BRAF inhibitor here)
16 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, MD Professor of Haematology Department of Haematology Lille University Hospital Lille, France
17 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
18 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 Protocol Newly Diagnosed MM Patients 65–75 Years
Arm MP Arm MP-T Arm MEL100 Overall Survival According to Treatment MP 1 MP VAD 1 1 + MP 2 VAD 2 Thalidomide 0.8 400 mg/d MP 3 Cyclophosphamide 0.6 3g/m2 + lenograstim + PBSC harvest 0.4
Proportion Survival time Treatment O/N median ± se (month) MEL 100 mg/m2 0.2 MP 97/196 32.2 ± 4.2 + PBSC + MP 12 MP-T 43/125 53.6 ± 5.2 lenograstim MEL100 66/126 38.6 ± 3.4 0 0 122436486072 MEL 100 mg/m2 Time From Randomization (month) + PBSC + lenograstim Facon T et al. Lancet. 2007;370:1209.
19 IFM 2017 Study
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.
Arm A
IRD2 IRD2 IRD2 Collection IRD2 IRD2 IRD2 IRD2 IRD2 DR maintenance
Arm B
IRD2 IRD2 IRD2 Collection ASCT IRD2 IRD2 DR maintenance
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.
20 FIRST (IFM2007-01/MM-020): Study Design
Screening LT Follow-Up Active Treatment + PFS Follow-Up Phase
LEN + LoDEX Continuously Arm A LENALIDOMIDE 25 mg D1-21/28 Rd Continuous LoDEX 40 mg D1, 8, 15 & 22/28
LEN + LoDEX 18 Cycles (72 wks) LENALIDOMIDE Arm B 25 mg D1-21/28 Rd18 LoDEX 40 mg D1, 8, 15 & 22/28
MEL + PRED + THAL 12 Cycles2,3 (72 wks) and PD, OS,
Arm C MELPHALAN 0.25 mg/kg D1-4/42 Subsequent AMT MPT PREDNISONE 2 mg/kg D1-4/42 RANDOMIZATION 1:1:1 RANDOMIZATION THALIDOMIDE 200 mg D1-42/42 PD or Unacceptable Toxicity Unacceptable PD or 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. 1. Benboubker L et al. N Engl J Med. 2014;371:906. • Stratification: age, country, and ISS stage 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.
IFM 2007-01 FIRST Trial: PFS and OS
PFS as per investigator assessment1 OS2 Data cut-off: 3 March 2014 Data cut-off: 3 March 2014 Median follow-up: 45.5 mos Median follow-up: 45.5 mos 697 deaths (43% of ITT) Median PFS Median OS 4-year OS Rd (n = 535) 26.0 mos Rd (n = 535) 58.9 mos 60% 1.0 Rd18 (n = 541) 21.0 mos 1.0 Rd18 (n = 541) 56.7 mos 57% MPT (n = 547) 21.9 mos MPT (n = 547) 48.5 mos 51% 0.8 0.8
0.6 0.6
0.4 33% 0.4 Hazard ratio Hazard ratio 0.2 Rd vs MPT: 0.69; P<0.001 14% 0.2 Rd vs MPT: 0.75; P=0.002 Survival Probability Survival Survival ProbabilitySurvival Rd vs Rd18: 0.71; P<0.001 Rd vs Rd18: 0.91; P=0.30 Rd18 vs MPT: 0.99; P=0.866 13% 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72 PFS (months) OS (months)
1. Lenalidomide European Public Assessment Report. March 2015. 2. Facon T et al. J Clin Oncol. 2015;33: Abstract 8524.
21 IFM 2007-01, FIRST Trial: Age Analysis, OS
Median follow-up of 45.5 months as of 3 March 2014 Age ≤75 Years Age >75 Years Median, 4-yr, Median, 4-yr, months % months % 100 Rd continuous 60.9 64 100 Rd continuous 52.3 52 Rd18 60.6 61 Rd18 45.7 48 80 MPT 55.3 57 80 MPT 37.8 39
60 60
40 40 Hazard ratio (95% CI) Hazard ratio (95% CI) Patients (%) Patients Rd vs MPT: 0.76 (0.60–0.96) (%) Patients Rd vs MPT: 0.72 (0.54–0.96) 20 20 Rd vs Rd18: 0.90 (0.71–1.15) Rd vs Rd18: 0.91 (0.68–1.22) Rd18 vs MPT: 0.84 (0.66–1.06) Rd18 vs MPT: 0.79 (0.60–1.04 0 0 0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66 OS (months) OS (months) Rd 349 329 311 295 272 249 231 171 110 55 12 0 Rd 186 136 108 88 70 57 44 27 12 4 0 Rd18 348 328 309 287 265 246 229 164 99 49 13 0 Rd18 193 137 106 83 49 31 23 15 7 4 0 MPT 359 330 306 291 262 244 223 161 88 41 8 0 MPT 188 125 94 72 54 37 26 20 7 3 0
MPT, melphalan, prednisone, thalidomide; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles. Hulin C et al. Haematologica. 2015;100: Abstract S429.
a National Cancer Institute program SWOG S0777: Study Design
Eight 21-day cycles of VRd Rd maintenance Bortezomib 1.3/mg2 IV until PD, toxicity, Days 1, 4, 8, and 11 or withdrawal Randomization Lenalidomide 25 mg/day PO N = 525 Days 1–14 Stratification: Dexamethasone 20 mg/day PO Lenalidomide 25 mg • ISS (I, II, III) Days 1, 2, 4, 5, 8, 9, 11, 12 After PO days 1–21 • Intent to induction Dexamethasone 40 mg transplant at Six 28-day cycles of Rd PO days 1, 8,15, 22 progression (yes/no) Lenalidomide 25 mg/day PO Days 1-21 Dexamethasone 40 mg/day PO Days 1, 8, 15, 22 • All patients received aspirin 325 mg/day
• VRd patients received HSV prophylaxis Durie B et al. Blood. 2015;126: Abstract 25.
22 SWOG S0777: PFS and OS by a National Cancer Institute program Assigned Treatment Arm
PFS by assigned treatment arm OS by assigned treatment arm Median in Median in 100 Events/N months 100 Events/N months 90 VRd 137/242 43 (39, 52) 90 VRd 76/242 75 (66, -) Rd 166/229 30 (25, 39) Rd 100/229 64 (56, -) 80 80 70 70 60 60 50 50 VRd 40 40 Rd
Patients (%) 30 VRd Patients (%) 30 20 HR = 0.712 (0.560, 0.906)* 20 HR = 0.709 (0.516, 0.973)* Log-rank P value = 0.0018 Rd Log-rank P value = 0.0250 10 (one sided)* 10 (two sided)* 0 0 024487296 024487296 Months From Registration Months From Registration
* Stratified Durie B et al. Blood. 2015;126: Abstract 25.
Combination Study of Carfilzomib, Lenalidomide, and Dexamethasone in Patients With NDMM: Study Design
Eight 28-day cycles Stem cell harvest after 4 cycles of KRd Key inclusion for transplant-eligible patients Primary criteria Extended dosing end point • Age ≥18 years KRd 24 cycles • Rate of PN • NDMM with grade ≥ 3 measurable Carfilzomib disease 20/36 mg/m2 IV, days 1, 2, 8, 9, 15, 16 Secondary 2 If ≥SD • Creatinine Cycle 1, days 1, 2: carfilzomib dose 20 mg/m Lenalidomide end point clearance ≥60 10 mg/day PO, • MRD* mL/min Lenalidomide 25 mg/day PO, days 1–21 days 1–21 • Response • ECOG PS 0–2 Lenalidomide was administered on days 2–21 rates • ANC ≥1.0 × 109/L, in cycle 1 alone and on days 1–21 of cycles 2–8 • Progression- hemoglobin ≥8.0 free survival g/dL, platelet Dexamethasone • Duration of count ≥75 × 109/L 20/10 mg IV or PO, days 1, 2, 8, 9, 15, 16, 22, 23 response • Adequate hepatic Cycles 1–4: dexamethasone dose 20 mg; • Safety function cycles 5–8: dexamethasone dose 10 mg.
*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. Korde N et al. JAMA Oncol. 2015;1:746.
23 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?
24 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
IMWG Frailty Scale1 Proxy for MM-020 Analysis Score Age Age ≤75 yrs ≤75 years 0 76−80 yrs 76−80 yrs 1 >80 yrs >80 yrs 2 Activity of Daily Living score EQ-5D: Self Care score >4 1 (no problem) 0 ≤4 2−3 (moderate or severe problem) 1 Instrumental Activity of Daily Living score EQ-5D: Usual Activities score 5 1 (no problem) 0 ≤5 2−3 (moderate or severe problem) 1 Charlson Comorbidity Index score Charlson Comorbidity Index score ≤1 ≤1 0 ≥2 ≥2 1 Total 0: Fit 1: Intermediate 1. Palumbo A et al. Blood. 2015;125:2068. ≥2: Frail Facon T et al. Blood. 2015;126: Abstract 4239.
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
1.0 1.0
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2 Survival Probability Survival Survival Probability Survival 0 0 0 20 40 60 80 0 20 40 60 80 PFS By Investigator, mos OS, mos
Severity n Median PFS, mos (95% CI) HR (95% CI) Severity n Median OS, mos (95% CI) HR (95% CI) Fit + ISS I 84 34.1 (25.6-43.7) Fit + ISS I 84 NR 0.71 (0.50-0.99) 0.57 (0.33-1.00) Fit + ISS II/III 171 23.3 (21.2-30.2) Fit + ISS II/III 171 NR Int + ISS I/II 298 27.7 (24.6-30.4) Int + ISS I/II 298 63.1 (58.2-NR) 0.63 (0.49-0.80) 0.43 (0.32-0.59) Int + ISS III 150 19.2 (17.6-21.3) Int + ISS III 150 44.3 (33.5-56.1) Frail + ISS I/II 437 23.0 (20.5-25.8) 0.69 (0.58-0.82) Frail + ISS I/II 437 58.9 (49.5-NR) Frail + ISS III 377 17.1 (14.1-19.0) 0.57 (0.47-0.69) Frail + ISS III 377 35.6 (32.5-40.6)
Facon T et al. Blood. 2015;126: Abstract 4239.
25 UKMRA Myeloma XIV: FITNESS Frailty-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
Trial design Transplant-ineligible NDMM Frailty indexing (FI) performed in all patients at baseline 1:1 REACTIVE ADAPTIVE
Non-adjusted Frailty index–adjusted therapy
1:2 FIT UNFIT FRAIL CRDa IRDa 1:2 1:2 1:2 INDUCTION C – 500 mg D1 & D8 CRDa IRDa CRDa IRDa CRDa IRDa R – 25 mg D1–21 D – 20 mg FIT: C – 500 mg D1 & D8, R – 25 mg D1-21, D – 20 mg/wk, I – 4 mg/wk I – 4 mg weekly UNFIT: C – 350 mg D1 & D8, R – 15 mg D1-21, D – 10 mg/wk, I – 3 mg/wk FRAIL: C – 250 mg D1 & D8, R – 10 mg D1-21, D – 10 mg/wk, I – 3 mg/wk TREAT TO MAXIMUM RESPONSE (6–8 cycles)
1:1 Lenalidomide Ixazomib/Lenalidomide MAINTENANCE
26 Treatment of MM in Elderly Patients: Landscape and Perspectives
VMP Alternating VMP – Daratumumab1 regimens8 ? < # Vd ? VRD2,3 Rd – Ixazomib4 MP < MPT < Rd Rd – Elotuzumab5 < MPR-R Rd – Daratumumab6 MPT-T MP – Carfilzomib7
1. DaraVMP vs. VMP. Available at: https://clinicaltrials.gov/ct2/show/NCT02195479 2. 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.
Phase 3 Rd-Based Continuous Studies for Elderly Patients
NCT01335399 NCT01850524 NCT02252172 Elotuzumab Ixazomib Daratumumab
Rd ELO-Rd Rd Ixazomib-Rd Rd DARA-Rd R: 25 mg PO ; D1–21 ELO: 10 mg/kg; D1, R: 25 mg PO ; D1–21 Ixazomib: 4 mg R: 25 mg PO ; D1–21 DARA: 16 mg/kg q1wk for 8 wks; q2wk DEX: 40 mg PO ; D1, 8, 15 & 22 (cycles 1– DEX: 40 mg PO ; D1, R: 25 mg DEX: 40 mg PO ; D1, for 16 wks; q4wk 8, 15 & 22 2); D1 & 15 (cycles 8, 15 & 22 DEX: 40 mg; D1, 8, 8, 15 & 22 3–18); 20 mg/kg on thereafter 28-d cycles until PD 28-d cycles/18 mos 15 & 22 28-d cycles until PD D1 (cycles ≥ 19) R: 25 mg PO d; 28-d cycles/18 mos R: 25 mg, D1–21 D1–21 DEX: 40 mg D1, 8, 15 DEX: 40 mg PO d; & 22 (cycles 1–2); DEX Discontinued DEX Discontinued D1, 8, 15 & 22 D1 & 15 (cycles 3– 18); D1 (cycles ≥ 19) Placebo + R Ixazomib+ R 28-d cycles, until PD R 10 mg Ixazomib: 3 mg 28-d cycles; Rd R: 10 mg Until PD for up to 2 years; Until PD DARA until PD • Primary end point for all studies is PFS 1. 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.
27 Patient Case 2
Robert M. Rifkin, MD Associate Chair – US Oncology Research Disease Lead – Multiple Myeloma Attending Physician Rocky Mountain Cancer Centers Denver, 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.
28 Case Study 2
52-year-old woman referred for workup of anemia.
Past medical Past surgical Family Social Physical history history history history exam • None • Appendectomy • Sister-in-law • Married, works • Normal and varicose has myeloma at a uniform • ROS: negative vein stripping and failed two supply firm except for mild SCTs • Nonsmoker, fatigue rare social alcohol • No substance use
Case Study 2: Labs
Actual Normal Actual Normal Value Range Value Range WBC (103/mL) 3.7 (4–11) Quantitative IgG (mg/dL) 3,431 (H) (700–1,600) Hemoglobin (g/dL) 9.8 (13–16) Igs + serum IgA (mg/dL) 158 (H) (70–400) CBC with immuno- Hematocrit (%) 30.1 (34–45) differential fixation IgM (mg/dL) 40 (H) (40–230) Platelets (103/mL)* 278 (150–400) Kappa quant FLC (mg/L) 437.6 (H) (3.30–19.40) Neutrophils (103/mL) 5.6 (1.9–7.5) Lambda quant FLC (mg/L) 13.67 (H) (5.71–26.30) BUN (mg/dL) 16 (7–20) FLC Kappa/lambda quant FLC 31.9 (H) (0.26–1.65) Creatinine (mg/dL) 0.8 (0.7–1.2) ratio CMP 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) IF- IgG SPEP M protein spike (g/dL) 2.6
*With normal iron studies
29 Case Study 2: Imaging and BM Biopsy
Bone BM Flow imaging biopsy cytometry Cytogenetics FISH* Skeletal survey • 40% cellular with • 2% events • 46, XX • Negative for gain • Indeterminate 30% plasma positive for of 1q21 lesions in right cells CD38, CD56, • Negative for loss intertrochanteric • Aspirate 24% CD138, and of chromosome area plasma cells cytoplasmic 13q DEXA scan kappa light • Negative for loss chains • Osteopenia of TP53 and ATM • Negative for IgH (14q32) and IGH/CCND1 [t(11;14)] rearrangement *CD138 selected plasma cells
Strategies to Prolong Response Amrita Y. Krishnan, MD Professor, Department of Hematology & Hematopoietic Cell Transplantation Director, Judy and Bernard Briskin Center for Multiple Myeloma Research City of Hope Medical Center Duarte, California
30 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 [6] • Myeloma XI 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.
IFM/DFCI 2009 Study Schema
Registration, newly diagnosed MM pts 65 years (ASCT candidates) 1 cycle RVD ARM A: Late transplant arm Randomize, stratification ISS & FISH ARM B: Early transplant arm
RVD, cycles 2, 3 Induction RVD, cycles 2, 3
CY (3g/m2) + G-CSF CY (3g/m2) + G-CSF MOBILIZATION PBSC collection MOBILIZATION Goal: 5 ×106 cells/kg Goal: 5 ×106 cells/kg
Melphalan 200 mg/m2 + ASCT Consolidation RVD × 5 RVD × 2 Maintenance Lenalidomide (10–15 m/d) Lenalidomide (10–15 mg/d) 12 mos US len maintenance till progression 12 mos SCT at relapse MEL 200 mg/m2 if <65 yrs, ≥65 yrs 140 mg/m2 Attal M et al. Blood. 2015;126: Abstract 391.
31 IFM 2009: Best Response
RVD Arm Transplant Arm N=350 N=350 P Value CR (%) 49 59 VGPR (%) 29 29 0.02 PR (%) 20 11 Attal M et al. Blood. 2015;126: Abstract 391. IFM 2009: PFS (9/2015) 100 HDT 90 no HDT 80 70 60 P<0.001 50 40 Patients (%) 30 20 10 0 0 12 24 36 48 Months of Follow-Up N at risk HDT 350 309 261 153 27 no HDT 350 296 228 128 24 Attal M et al. Blood. 2015;126: Abstract 391. 32 IFM 2009: OS (9/2015) 100 90 80 70 60 P NS 50 HDT 40 no HDT Patients (%) 30 20 10 0 0 12 24 36 48 Months of Follow-Up N at risk HDT 350 328 309 226 55 no HDT 350 338 320 244 56 Attal M et al. Blood. 2015;126: Abstract 391. IFM 2009: Cause of Death (9/2015) RVD Arm Transplant N=48 N=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. 33 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 RVD 4, 42-day cycles R2 R1 No Len HDM + Single ASCT CyBorD RVD 3-4, 21-day cycles HDM + Double ASCT Consolidation Maintenance Induction VMP HDM (n=497) (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) 0.003 Probability of achieving ≥VGPR (%) 74 85.5 OD 1.90 (1.42-2.54) <0.001 Upfront HDM and ASCT significantly improved PFS and increased the rate of high quality responses. Cavo M et al. Blood. 2016;128: Abstract 673. High Dose Therapy: Single vs Tandem EMN02/HO95 VMP 4, 42-day cycles Median PFS (27-mos f/up): R1 HDM + Single ASCT • ASCT1, 45 mos CyBorD • ASCT2, NR 3-4, 21-day cycles HDM + Double ASCT Lenalidomide AM Stamina Maintenance Estimated PFS (38-mos): Register and MEL Lenalidomide ACM Randomize 200mg/m2 VRD x 4 Maintenance • TAM, 56% • ACM, 57% MEL Lenalidomide • AM, 52% 200mg/m2 Maintenance TAM Cavo M et al. Blood. 2016;128: Abstract 991. Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1. 34 Increase Depth of Response: MRD RVD Arm Transplant Arm 100 100 MRD pos MRD pos 90 MRD neg 90 MRD neg 80 80 70 70 60 60 50 50 P<0.001 P<0.001 40 40 Patients (%) Patients 30 (%) Patients 30 20 20 10 10 0 0 012243648 012243648 Months of Follow-Up Months of Follow-Up N at risk N at risk MRD pos 89 75 54 22 2 MRD pos 65 57 43 30 4 MRD neg 140 135 113 72 14 MRD neg 172 166 151 86 17 Attal M et al. Blood. 2015;126: Abstract 391. Avet-Loiseau H et al. Blood. 2015;126: Abstract 191. MRD: Still ?? Advantages Disadvantages Flow cytometry Flow cytometry • Feasible in 100% of patients • Fresh sample (<24–48 h) • Does not require diagnostic sample • Sensitivity 10-4–10-5 • Widely available/low cost • Lack of standardization (operator) NGS (adaptive) NGS (adaptive) • Sensitivity <10-6 • Requires diagnostic sample (clone • Frozen samples ID) • Fully standardized • Feasibility Paiva B et al. Clin Cancer Res. 2015;21:2001. Nishihori T et al. Curr Hematol Malig Rep. 2016;11:118. 35 Sensitivity Matters MRD at post-maintenance 1.0 0.9 <10-6 0.8 0.7 0.6 0.5 [10-6; 10-5] 0.4 [10-5; 10-4] Progression (%) Progression Patients Without P value (trend): P<0.0001 0.3 ≥10-4 0.2 0 6 12 18 24 30 36 42 48 Months Since Randomization N at risk (events) <10-6 86(0) 86 86(0) 86(0) 86(0) 77(5) 61(3) 36(5) (0) 10 [10-6; 10-5] 29(0) 29 29(0) 29(0) 28(0) 22(5) 16(3) 4(4) (1) 1 [10-5; 10-4] 23(0) 23 23(0) 23(0) 22(1) 19(3) 14(2) 3(5) (0) 2 [10-4; 10-3] 40(0) 40 40(0) 40(0) 33(6) 23(9) 15(6) 4(4) (1) 2 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]. 36 IMWG Criteria for Response and MRD Assessment in MM Sustained MRD-negative • 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) Flow 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 Sequencing 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 Imaging plus 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 Kumar S et al. Lancet Oncol. 2016;17:e328. Prolong Response: Consolidation BMT CTN 0702 Lenalidomide Maintenance AM Register and Lenalidomide MEL 200mg/m2 VRD x 4 Randomize Maintenance ACM N=750 pts (250 in each arm) MEL Lenalidomide 200mg/m2 Maintenance TAM ASCT with Len Consolidation with Tandem ASCT with Maintenance Len Maintenance Len Maintenance (AM) (ACM) (TAM) N 257 254 247 38-mo PFS (%) 52 57 56 Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1. 37 Prolong Response: Consolidation EMN02/HO95 VMP RVD 4, 42-day cycles R1 R2 Len HDM + Single ASCT No CyBorD RVD 3-4, 21-day cycles HDM + Double ASCT Consolidation Maintenance Induction No P Value Consolidation Consolidation 3-year PFS (%) 65 60 0.045 Not retained in high risk cytogenetics (0.91) Sonneveld P et al. Blood. 2016;128: Abstract 242. Prolong Response: Consolidation Phase 2 US Study1 Induction Consolidation Maintenance (Cycles 1–4) (Cycles 5–8) (Cycles 9–18) Post Post KRd Post KRd SCT Consol Maint Indefinite MRD (%) Maintenance -- 82/66 90/71 KRd ASCT KRd KRd MFC/NGS Lenalidomide sCR (%) 20 69 82 Phase 2 IFM Study2 Induction Consolidation Post Post (Cycles 1–4) (Cycles 5–8) Maintenance Induction Post ASCT Consol Lenalidomide, (n=46) (n=42) (n=42) KRd ASCT KRd 1 Year MRD (%) by flow 63 81 89 CR + sCR (%) 26 45 69 KRd is now being compared with ORR (%) 98 98 98 VRd in a randomized clinical trial. 1. Zimmerman T et al. Blood. 2016;128: Abstract 675. 2. Roussel M et al. Blood. 2016;128: Abstract 1142. 38 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. 39 HOVON Study Schema MM Stage II or III, Age 18–65 1.3 mg/m2 Randomization Bortezomib i.v., 2x/w 2 3 × VAD 3 × PAD Doxorubicin 9 mg/m Dexameth 40 mg CAD + GCSF CAD + GCSF MEL 200 + PBSCT MEL 200 + PBSCT In GMMG 2nd Allogeneic In GMMG 2nd MEL 200 + PBSCT transplant MEL 200 + PBSCT Thalidomide Bortezomib maintenance maintenance 50 mg/day for 1.3 mg/m2/2 weeks 2 years for 2 years Sonneveld P et al. J Clin Oncol, 2012;30:2946. OS by Treatment Arm Overall Survival • OS at 96 m: 48% Randomization Arm 100 vs 45% 75 • HR: 0.87, 95% CI B: PAD 0.71–1.04; P=0.22 50 A: VAD ND 25 A: VAD 414 217 B: PAD 413 204 • RMST8y: 4.8 Cumulative Percentage Cumulative Cox LR Stratified P=0.22 0 months (95% CI 024487296 Months 0.2–9.5; P=0.04) Sonneveld P et al. Blood. 2015;126: Abstract 27. 40 Studies Included in Meta-Analysis CALGB 100104 IFM 2005-02 GIMEMA (RV-MM-PI-209) (accrual 8/2005–11/2009) (accrual 6/2006–8/2008) (accrual 11/2007–7/2009) INDUCTION INDUCTION 2 × 2 DESIGN ASCT ASCT LEN + DEX × 4 1:1 RANDOMIZATION 1:1 RANDOMIZATION INDUCTION “NO EVIDENCE OF PD” “NO EVIDENCE OF PD” ASCT MPR: 6 COURSES LEN: 2 COURSES PLACEBO LEN MNTCa PLACEBO LEN MNTCa NO TREATMENT LEN MNTCb NO TREATMENT LEN MNTCb (n=229) (n=231) (n=307) (n=307) (n=68) (n=67) INTERIM ANALYSIS ANDINTERIM UNBLINDING ANALYSIS AND UNBLINDING PRIMARY ANALYSIS Dec 2009 Jan 2010 CROSSOVER NO CONTINUED CONTINUED CONTINUED CONTINUED BEFORE PD CROSSOVER TREATMENT TREATMENT TREATMENT TREATMENT ALLOWED BEFORE PD ALLOWED ALL TREATMENT DISCONTINUED Jan 2011 Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT 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. Attal M et al. J Clin Oncol. 2016;34: Abstract 8001. 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 1.0 7-yr OS 0.8 62% 0.6 0.4 50% Survival Survival N=1,209 Lenalidomide Control Probability Median OS NE 86.0 (95% CI), mos (NE–NE) (79.8–96.0) 0.2 HR (95% CI) 0.74 (0.62–0.89) Pvalue 0.001 0.0 0 102030405060708090100110120 Overall Survival, mos Patients at risk 605 578 555 509 474 431 385 282 200 95 20 1 0 604 569 542 505 458 425 350 271 174 71 10 0 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). Attal M et al. J Clin Oncol. 2016;34: Abstract 8001. 41 Cumulative Incidence of Second Primary Malignancies Hematologic Solid Tumor 1.00 1.00 0.80 0.80 Lenalidomide Lenalidomide 0.60 Control 0.60 Control a 0.40 HR (95% CI): 2.03a (1.14–3.61) 0.40 HR (95% CI): 1.71 (1.04–2.79) P=0.015b P=0.032b 0.20 0.20 Cumulative Incidence Incidence Cumulative Cumulative Incidence Incidence Cumulative 0.0 0.0 0 1224364860728496108 0 1224364860728496108 Time to Hematologic SPM Onset, mos Time to Solid Tumor SPM Onset, mos Patients 586 559 514 465 422 365 251 139 38 1 Patients 586 554 508 458 415 360 251 136 35 0 at risk 602 559 525 468 428 340 248 119 28 0 at risk 602 559 520 461 417 328 241 117 28 0 a HR based on Cox proportional hazards model. b P value is based on log-rank test. 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 TE (n=828) TNE (n=722) Maint No Maint Maint No Maint P Value Median PFS (mos) 60 28 26 12 <0.0001 • Hematologic second primary malignancy 0.9% with maintenance vs 0.3% with no maintenance Jackson G et al. Blood. 2016;128: Abstract 1143. 42 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 43 Patient Case 3 Robert M. Rifkin, MD Associate Chair – US Oncology Research Disease Lead – Multiple Myeloma Attending Physician Rocky Mountain Cancer Centers Denver, 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 44 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 45 Case Study 3: Labs Actual Normal Actual Normal Value Range Value Range WBC (103/mL) 3,400 (4–11) Quantitative IgG (mg/dL) 8,431 (H) (700–1,600) Hemoglobin (g/dL) 9.9 (13–16) Igs + serum IgA (mg/dL) <30 (L) (70–400) CBC with immuno- Hematocrit (%) 31.6 (34–45) differential fixation IgM (mg/dL) <5 (L) (40–230) Platelets (103/mL) 164 (150–400) Kappa quant FLC (mg/L) 760.4 (H) (3.30–19.40) Neutrophils (103/mL) 2.1 (1.9–7.5) Lambda quant FLC (mg/L) 13.67 (H) (5.71–26.30) BUN (mg/dL) 24 (7–20) FLC Kappa/lambda quant FLC 55.62 (H) (0.26–1.65) Creatinine (mg/dL) 0.85 (0.7–1.2) ratio CMP 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) IF- IgG SPEP M protein spike (g/dL) 4.5 New Agents, Classes in the Relapsed Setting Faith E. Davies, MBBCh, MRCP, MD, FRCPath Professor of Medicine Medical Director, Myeloma Institute University of Arkansas for Medical Sciences Little Rock, Arkansas 46 Factors Affecting Treatment Decisions in RRMM First-line Salvage therapies therapy Patient-related Class of prior Number and factors: age, Aggressiveness therapy*; degree degree of PS, counts, of disease and of response to relapses and PN, VTE, RI, prognostic prior therapy; refractory cytogenetic features PFS; tolerability disease profile, of prior therapy extramedullary (treatment- involvement, related AEs) etc Disease progression *IMiD-based, proteasome-based, alkylators, dexamethasone. Current Therapies for RRMM 1–3 Lines Can Be Classified by the Drug’s Mechanism of Action Proteasome inhibitors Bortezomib Carfilzomib Ixazomib Immunomodulators Thalidomide Lenalidomide Pomalidomide HistoneCritical deacetylase to understandPanobinostat treatment patterns specific to your own country/region as Monoclonal antibodiesdrug approvalDaratumumab variabilityElotuzumab exists Alkylators High-dose melphalan Bendamustine Cyclophosphamide Steroids Dexamethasone Prednisolone Methyl prednisolone 47 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 48 Plethora of New Randomized Studies to Help Guide Treatment Decisions Control Arm Comparator Arm Trial Name Carfilzomib, lenalidomide, and dexamethasone ASPIRE Lenalidomide and Elotuzumab, lenalidomide, and ELOQUENT 2 dexamethasone dexamethasone Ixazomib, lenalidomide, and dexamethasone TOURMALINE 1 Bortezomib and Carfilzomib and dexamethasone ENDEAVOR dexamethasone Panobinostat, bortezomib, and dexamethasone PANORAMA 1 Dexamethasone Pomalidomide and dexamethasone MM03 NIMBUS No transplant High-dose melphalan Myeloma X Differences Between Studies in Baseline Characteristics Study N Treatment Carfilzomib-lenalidomide-dexamethasone (KRd) vs ASPIRE1 792 lenalidomide-dexamethasone (Rd) Elotuzumab-lenalidomide-dexamethasone (Erd) vs ELOQUENT-22 646 lenalidomide-dexamethasone (Rd) Ixazomib-lenalidomide-dexamethasone (Ird) TOURMALINE-MM13 722 vs placebo-lenalidomide-dexamethasone (Rd) Carfilzomib-dexamethasone (Kd) ENDEAVOR4 929 vs bortezomib-dexamethasone (Vd) Proportion of patients with refractory disease, disease stage ISS III, low creatinine clearance, high risk cytogenetics 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. 49 ASPIRE: Carfilzomib-Lenalidomide-Dexamethasone (KRd) vs Lenalidomide-Dexamethasone (Rd) • Phase 3, open-label, randomized, multicenter study KRd KRd Rd CFZ: 20/27 mg/m2, d 1–2*, 8–9, 15–16 CFZ: 27 mg/m2, d 1, 2, 15, 16 LEN: 25 mg, d 1–21 N=792 LEN: 25 mg, d 1–21 RRMM patients LEN: 25 mg, d 1–21 DEX: 40 mg, DEX: 40 mg, d 1, 8, 15, 22 DEX: 40 mg, d 1, 8, 15, 22 d 1, 8, 15, 22 Six 28-day cycles Until PD • Prior treatment Twelve 28-day cycles with 1–3 regimens Rd • ≥ PR to ≥1 prior LEN: 25 mg, d 1–21 regimen DEX: 40 mg, d 1, 8, 15, 22 28-day cycles until progression • Stratified for previous Bortezomib therapy • Patients received antiviral and antithrombotic prophylaxis • Primary end point: PFS • Secondary end points: OS, ORR, DoR, HRQoL, safety *Carfilzomib is administered at 20 mg/m2 on Days 1 and 2 Stewart AK et al. N Engl J Med. 2015;372:142. ASPIRE: KRd vs Rd Efficacy KRd Rd HR; (n=396) (n=396) P value sCR HR = 0.69; Response rates Median PFS, months 26.3 17.6 P=0.0001* CR 100 VGPR Median OS, months NR NR HR = 0.79; ORR: 87.1% 2-year OS, % 73.3 65.0 P=0.04† PR 14.1 Time to response, months 1.0 1.0 ─ 80 ORR: 66.7% 4.3 Median DOR, months 28.6 21.2 NR 60 17.7 ≥PR, ≥VGPR 5.1 and ≥CR: • Median follow-up was 32.3 months for KRd and 31.5 P<0.001 40 31.1 months for Rd 38.1 Patients, % • PFS benefit for KRd was observed across all 20 predefined subgroups ‡ 26.3 17.2 0 KRd Rd *Prespecified stopping boundary was met (n=396) (n=396) † 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. 50 ASPIRE: KRd vs Rd Progression-Free Survival Figure 1, page 148 Stewart AK et al. N Engl J Med. 2015;372:142. ELOQUENT 2: Elotuzumab-Rd (ERd) vs Rd ERd (n = 321) ELO: 10 mg/kg, d1, 8, 15, 22 IV (cycles 1–2); d1, 15 (cycles ≥ 3); LEN: 25 mg, d1–21 N=646 DEX: weekly equivalent, 40 mg RRMM 28-day cycles until progression 1–3 prior lines Not LEN-refractory Rd (n = 325) LEN: 25 mg, d1–21 DEX: 40 mg, d1, 8, 15, 22 28-day cycles until progression • Primary end points: PFS, ORR • Secondary end points: OS, DoR, QoL, safety Lonial S et al. N Engl J Med. 2015;373:621. 51 ELOQUENT-2: ERd vs Rd Efficacy Responses1 P<0.001 ERd Rd HR; 100 (n=321) (n=325) P value a ORR 79% Median PFS, 0.73; 80 19.4 14.9 4 ORR 66%* months2 0.0014 0.62 60 28 7 Median TTNT, CR 33 21 (95% CI months2 21 0.50–0.77) 40 VGPR PR Median OS, 0.77; Patients (%) 43.7 39.6 months2 0.0257 20 46 38 Median DoR, 20.7 16.7 NR 0 months1 ERd Rd n=321 n=325 1. Lonial S et al. N Engl J Med. 2015;373:621-31. *Values may not sum due to rounding. 2. Dimopoulos MA et al. Blood. 2015;126: Abstract 28. ELOQUENT-2: ERd vs Rd Progression-Free Survival ERd Rd (n=321) (n=325) Figure 1, page 627 Median PFS, 19.4 (16.6−22.2) 14.9 (12.1−17.2) mos (95% CI) HR=0.73 (95% CI 0.60−0.89; P=0.0014) 3-yr PFS, % 26 18 Lonial S et al. N Engl J Med. 2015;373:621. Dimopoulos MA et al. Blood. 2015;126: Abstract 28. 52 TOURMALINE-MM1: Ixazomib-Lenalidomide- Dexamethasone vs Lenalidomide-Dexamethasone IRd LEN: 25 mg* PO d1–21 DEX: 40 mg PO d1, 8, 15, 22 IXA: 4 mg PO d1, 8, 15 N=722 28-day cycles FOLLOW-UP Pts with RRMM Every 4 weeks until 1–3 prior therapies 1:1 PD, then every 12 Not LEN- or PI-refractory Rd + Placebo weeks for OS LEN: 25 mg* PO d1–21 Stratification: DEX: 40 mg PO d1, 8, 15, 22 • Prior treatment Placebo: PO d1, 8, 15 • ISS stage 28-day cycles • PI exposure • 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). Moreau P et al. N Engl J Med. 2016;374:1621. TOURMALINE-MM1: IRd vs Rd Efficacy Summary Responses P<0.001 100 ORR 78%* a Table 2, page 1626 80 ORR 72% CR 12 7 VGPR 60 PR 36 32 Moreau P et al. N Engl 40 CR: P=0.019; J Med. 016;374:1621. Patients (%) 20 CR + VGPR: 30 33 P=0.014 0 IRd Rd n=360 n=362 *Values may not sum due to rounding. Moreau P et al. N Engl J Med. 2016;374:1621. 53 TOURMALINE-MM1: IRd vs Rd PFS Analysis Figure 1, page 1627 Moreau P et al. N Engl J Med. 2016;374:1621. • Consistent PFS benefit across pre-specified patient subgroups ENDEAVOR Study Design Kd Carfilzomib 56 mg/m2 IV Randomization 1:1 Days 1, 2, 8, 9, 15, 16 (20 mg/m2 Days 1, 2, cycle 1 only) N=929 Infusion duration: 30 minutes for all doses Stratification: Dexamethasone 20 mg Days 1, 2, 8, 9, 15, 16, 22, 23 • Prior proteasome 28-day cycles until disease progression or unacceptable toxicity inhibitor therapy • Prior lines of treatment Vd • ISS stage Bortezomib 1.3 mg/m2 (3–5 second IV bolus or subcutaneous injection) • Route of Days 1, 4, 8, 11 administration Dexamethasone 20 mg Days 1, 2, 4, 5, 8, 9, 11, 12 21-day cycles until disease progression or unacceptable toxicity BOR NAÏVE OR BOR SENSITIVE • Primary end point: PFS Dimopoulos MA et al. Lancet Oncol. 2016;17:27. 54 ENDEAVOR: Kd vs Vd in RRMM Progression-Free Survival • Median follow-up: 11.9 mos for Kd; 11.1 mos for Vd Kd Vd (n=464) (n=465) 100 Median PFS, months 18.7 9.4 (95% CI) (15.6−NE) (8.4−0.4) 80 Hazard ratio 0.53 (0.44−0.65) P value <0.0001 60 40 PFS (%) Kd 20 Vd 0 0 6 12 18 24 30 Time (years) • A consistent PFS benefit for Kd was observed across predefined subgroups *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. Dimopoulos MA et al. Lancet Oncol. 2016;17:27. PANORAMA 1: Panobinostat + Bortezomib and Dexamethasone vs Bortezomib and Dexamethasone • Multicenter, randomized, double-blind, placebo-controlled, phase 3 study Study population Treatment phase 1 (TP1) Treatment phase 2 (TP2) PanVD (21-day cycle) PanVD (42-day cycle) Panobinostat Panobinostat • N = 768 • 20 mg PO on d1, 3, 5, 8, 10, 12 • 20 mg PO as TP1 + on d22, 24, 26, 29, 31, 33 • 1–3 lines prior Bortezomib Bortezomib 2 2 therapy • 1.3 mg/m IV on d1, 4, 8, 11 • 1.3 mg/m IV d1, 8, 22, 29 Dexamethasone Dexamethasone • Measurable • 20 mg PO on d1, 2, 4, 5, 8, 9, 11, 12 • 20 mg PO on d1, 2, 8, 9, 22, 23, 29, 30 M protein component in R serum or Placebo + VD (21-day cycle) Placebo + VD (42-day cycle) urine at study Placebo Placebo screening Bortezomib Bortezomib • As above • As above • ECOG ≤2 Dexamethasone Dexamethasone • As above • As above • Primary end point: PFS San Miguel JF et al. Lancet Oncol. 2014;15:1195. 55 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 Figure 1, page 716 Richardson PG et al. Blood. 2016;127:713. San-Miguel JF et al. J Clin Oncol. 2015;33: Abstract 8526. Richardson PG et al. Blood. 2016;127:713. MM-003 NIMBUS: Pomalidomide Dexamethasone vs Dexamethasone 28-day cycles (n=302) Follow-up for POM*: 4 mg/day Day 1–21 + PD OS and SPM until LoDEX: 40 mg (≤75 years) 5 years post- 20 mg (>75 years) enrollment Day 1, 8, 15, 22 (N=455) (n=153) PD Companion trial HiDEX: 40 mg (≤75 years) MM-003C 20 mg (>75 years) POM 21/28 days RANDOMIZATION 2:1 Day 1–4, 9–12, 17–20 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 *Thromboprophylaxis was indicated for those receiving POM or with deep vein thrombosis history. San Miguel JF et al. Lancet Oncol 2013;14:1055. 56 MM-003 NIMBUS: POM + LoDEX vs HiDEX PFS Median 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 N=297 Bortezomib, doxorubicin, dexamethasone (PAD) Response ≥SD PD PBSC mobilization or CD34+ cells <2×106/kg R Off study Melphalan 200mg/m2 IV Cyclophosphamide ASCT 400 mg/m2 PO/week × 12 N=89 N=89 Follow-up Cook G et al. Lancet Oncol. 2014;15:874. 57 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 Table 3, page 151 Stewart AK et al. N Engl J Med. 2015;372:142. • 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 58 ENDEAVOR: Carfilzomib (Kd vs Vd) Cardiac Substudy Cardiac Substudy Overall Safety Population Kd (N=74) Vd (N=74) Kd (N=463) Vd (N=456) All grades n (%) n (%) n (%) 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 Table 3, page 630 Lonial S et al. N Engl J Med. 2015;373:621. Lonial S et al. N Engl J Med. 2015;373:621. 59 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 Oncol 2013;14:1055. 60 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, MD R.J. Corman Professor of Medicine Harvard Medical School Clinical Program Leader and Director of Clinical Research Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Boston, Massachusetts 61 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 62 WGS at Relapse Courtesy of Nikhil Munshi MD, DFCI Restoring Immune Function • Immunomodulatory drugs, other small molecules (eg, HDACi’s) • Monoclonal antibodies • Checkpoint inhibitors • Vaccines • Cellular therapies 63 Lenalidomide and Pomalidomide in MM C MM cells IL-6 B TNFα Bone marrow A IL-1β ICAM-1 stromal cells Bone marrow NFAT vessels PKC IL-2 IL-2 VEGF IFN NK cells bFGF PI3K CD28 NK-T cells CD8+ T D Dendritic cells cells E Hideshima T et al. Blood. 2000;96:2943. Davies FE et al. Blood. 2001;98:210. Lentzsch S et al. Cancer Res. 2002;62:2300. Gupta D et al. Leukemia. 2001;15:1950. LeBlanc R et al. Blood. 2004;103:1787. Mitsiades N et al. Blood. 2002;99:4525. Hayashi T et al. Br J Haematol. 2005;128:192. Immunomodulatory Agents IMiDs: Mechanism of Action Adapted from Figure, page 347 Stewart AK. Science. 2014;343:256. Krönke J et al Science. 2014;343:301. Lu G et al. Science 2014;343:305. 64 Model of Lenalidomide and Pomalidomide Costimulation of T Cells via Degradation of Aiolos and Ikaros Figure 9, page 819 Gandhi AK et al. Br J Haematol. 2014;164:811. Efficacy Results of POMALIDOMIDE + LoDEX in Advanced RRMM (Phase 2/3: MM002 & MM003) 50 MR PR 40 12 8 VGPR 30 CR/sCR ORR = 33% 20 30 24 ORR = 32% Response Percentage 10 3 1 7 0 1 2,3 MM-002MM (n=113) 002 MM-003MM (n=302) 003 MM-0021 MM-0032,3 MedianMM-002 follow-up, (n=113) months 1 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. 65 Monoclonal Antibodies Kill MM Through Multiple Mechanisms DIRECT EFFECTS INDIRECT EFFECTS Interferes with survival or delivers myeloma- Labels myeloma cells for Labels myeloma cells for Activates T cells by killing substances killing by complement killing by NK cells taking the brakes off Monoclonal antibody NK cell toxins Myeloma cell surface target Checkpoint inhibitor Complement Fc receptor Adapted from Richardson PG, ASH 2012 Elotuzumab: Immunostimulatory Mechanism of Action • 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 Elotuzumab Natural killer cell Natural killer cell SLAMF7 EAT-2 A Directly EAT-2 Granule synthesis activating natural Polarization killer cells Downstream Myeloma Degranulation activating signaling cell death cascade Perforin, SLAMF7 granzyme B release B Tagging for MyelomaMyeloma cell recognition cell (ADCC) 1. Hsi ED et al. Clin Cancer Res. 2008;14:2775. 2. Collins SM et al. Cancer Immunol Immunother. 2013;62:1841. 66 ELOQUENT-2: Primary Analysis Figure 1, page 627 Lonial S et al. N Engl J Med. 2015;373:621. From Table 2, page 629 ELOQUENT-2 demonstrated Lonial S et al. N Engl J Med. clinical benefits of E-Ld compared with lenalidomide 2015;373:621. and dexamethasone (Ld) alone1 1. Lonial S et al. N Engl J Med. 2015;373:621. Elotuzumab in High-Risk Patients ELOQUENT-2 Study Results Progression-Free Survival of Patients With del(17p) and t(4;14) Translocation 1.0 del(17p)+ 1.0 t(4;14)+ 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 E-Ld 0.5 0.4 0.4 0.3 Ld 0.3 E-Ld 0.2 0.2 Hazard ratio: 0.65 Hazard ratio: 0.53 Ld Probability Progression Free Progression Probability Probability Progression Free Progression Probability 0.1 (95% CI, 0.450.94) 0.1 (95% CI, 0.290.95) 0.0 0.0 0 2 4 6 8 101214161820222426283032343638 0 2 4 6 8 101214161820222426283032343638 PFS (months) PFS (months) Lonial S et al. J Clin Oncol. 2015;33. Abstract 8508. 67 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. 68 Daratumumab Monotherapy: Efficacy in Combined Analysis Figure 4, page 42 Usmani SZ et al. Blood. 2016;128:37. Usmani SZ et al. Blood. 2016;128:37. Daratumumab Phase 2 Study Single Agent in RRMM ORR by Subgroup 40 35 33 33 30 30 29 28 28 30 26 25 21 20 21 20 15 ORR, % 10 5 0 Refractory to Lonial S et al. Lancet. 2016;387:1551. 69 Daratumumab Phase 2 Study Single Agent in RRMM Progression-Free and Overall Survival 100 80 Figure 4, page 1558 Median PFS = 3.7 months 60 (95% CI, 2.8–4.6) Lonial S et al. Lancet. 40 Patients 2016;387:1551. and Alive and Alive (%) 20 Progression-Free 0 0 2 4 6 8 10 12 14 16 Months From Start of Treatment • 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. 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. 70 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 Design Multicenter, randomized, open-label, active-controlled phase 3 study DVd (n=251) Key eligibility R Primary end point criteria A Daratumumab (16 mg/kg IV) Every week: cycles 1–3 • PFS • RRMM N Every 3 weeks: cycles 4–8 Secondary end point D Every 4 weeks: cycles 9+ • ≥1 prior line of • TTP therapy O 1:1 Vel: 1.3 mg/m2 SC, days 1, 4, 8, 11: cycles 1–8 • OS M Dex: 20 mg PO-IV, days 1, 2, 4, 5, 8, 9, 11, 12: cycles 1–8 • ORR, VGPR, CR • Prior I • MRD bortezomib Vd (n=247) • Time to response exposure, but Z • Duration of response not refractory E Vel: 1.3 mg/m2 SC, days 1, 4, 8, 11: cycles 1–8 Dex: 20 mg PO-IV, days 1, 2, 4, 5, 8, 9, 11, 12: cycles 1–8 Statistical analyses • Cycles 1–8: repeat every 21 days • 295 PFS events: 85% • Cycles 9+: repeat every 28 days power for 4.3 month PFS Daratumumab IV administered in 1,000 mL to 500 mL; • Interim analysis: ~177 gradual escalation from 50 mL to 200 mL/hour permitted PFS events Palumbo A et al. N Engl J Med. 2016;375:754. 71 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 Vd in Pts With Relapsed or Refractory MM: CASTOR CASTOR PFS 1.0 1-year PFS* Median: not reached 0.8 60.7% 0.6 DVd 0.4 26.9% 0.2 Median: 7.2 months Vd Without Progression Without Proportion Surviving Proportion Surviving HR: 0.39 (95% CI, 0.28-0.53); P<0.0001 0 03691215 No. at risk Vd 247 182 106 25 5 0 DVd 251 215 145 56 11 0 61% reduction in the risk of disease progression or death for DVd vs Vd Palumbo A et al. N Engl J Med. 2016;375:754. 72 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. 73 Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX POLLUX Study Design R Key eligibility DRd (n=286) Primary end point criteria A Daratumumab 16 mg/kg V • PFS • RRMM • Qw in Cycles 1–2, q2w in Cycles 3–6, then q4w until N PD Secondary end point • ≥1 prior line of D therapy R 25 mg PO • TTP • Prior lenalidomide O • Days 1–21 of each cycle until PD • OS exposure, but not M 1:1 d 40 mg PO • ORR, VGPR, CR refractory • 40 mg weekly until PD • MRD • Patients with I creatinine clearance Z Rd (n=283) • Time to response • Duration of response ≥30 mL/min E R 25 mg PO • Days 1–21 of each cycle until PD Stratification factors Statistical analyses • No prior lines of therapy d 40 mg PO • 295 PFS events: 85% • ISS stage at study entry • 40 mg weekly until PD power for 7.7 month • Prior lenalidomide Cycles: 28 days PFS improvement • Interim analysis: ~177 Pre-medication for the DRd treatment group consisted of PFS events dexamethasone 20 mga, paracetamol, and an antihistamine. Dimopoulos M et al. N Engl J Med. 2016;375:1319. Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX POLLUX PFS 1.0 12-month PFS* 18-month PFS* 83% 78% 0.8 DRd 60% 0.6 52% 0.4 Rd Median PFS: 18.4 months 0.2 Without Progression Without Proportion Surviving HR: 0.37 (95% CI, 0.27–0.52); P<0.0001 0 No. at risk 0369121518 24 Rd 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 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 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 NR 17.4 ─ (mos) Dimopoulos M et al. N Engl J Med. 2016;375:1319. Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX POLLUX MRD-Negativity Rate 50 45 40 P<0.0001 DRd 35 P<0.0001 Rd 30% 30 25 23% P<0.0001 20 15 10% 10 8% MRD-negative Rate (%) Rate MRD-negative 5% 5 2% 0 MRD-neg (10-4) MRD-neg (10-5) MRD-neg (10-6) Dimopoulos M et al. N Engl J Med. 2016;375:1319. 75 Daratumumab in High-Risk Patients Daratumumab Phase 2 Study Single Agent in RRMM ORR by Subgroup 40 35 33 33 30 30 29 28 28 30 26 25 21 20 21 20 15 ORR, % 10 5 0 Refractory to Lonial S et al. J Clin Oncol. 2015;33. Abstract LBA 8512. Isatuximab CD38 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,6 Jonathan 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 76 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 cohorts Richter JR et al. J Clin Oncol. 2016;34: Abstract 8005. Immune Suppressive Microenvironment in MM pDC IL-6, IL-10, TGFβ, PGE, ARG1, NO, ROS, COX2 MDSC TAM PD-L1 PD-L1 Depletion of cysteine pDC, MDSC induced immune suppression PD1 PD1 NKT PD-L1 PD1 CD8 B PD1 MM NK Treg PD1 CD4 MM MM MM induced MM PD-L1 immune suppression Tumor promotion and induction of PD-L1 expression Stroma Görgün GT et al. Blood. 2013;121:2975. 77 Immune Checkpoint Inhibitors in MM 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 for Relapsed/Refractory Multiple Myeloma Keynote-023: Pembrolizumab + Phase 2 of Pembrolizumab + Lenalidomide and Pomalidomide and Dexamethasone1 Dexamethasone2 RRMM for whom ≥2 prior therapies, RRMM for whom ≥2 prior therapies, Patient population including a proteasome inhibitor and including a proteasome inhibitor and an IMiD, have failed 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 11 of 22 evaluable patients Response 17 patients; 76% response rate (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. 78 Durvalumab Figure 1, page 475 Ibrahim R et al. Semin Oncol. 2015;42(3):474. Harnessing the Immune System to Fight Myeloma Types of Immunotherapy, Immuno-Oncology Passive Active Monoclonal Chimeric antigen Vaccines (therapeutic antibodies receptor (CAR) T cells not preventive) Direct effects Monoclonal antibody 1. Extract WBCs from patient 2. Modify and Antigen expand cells ADCC in lab Fc receptor CDC Myeloma cell 3. Infuse MM-targeted C1q cells back to Lysis NK cell MAC patient Cell death 79 Phase 1 Trial of Vaccination With DC/MM Fusions in RRMM • Well tolerated, no autoimmunity • Induced tumor reactive lymphocytes in a majority of Figure 1, page 396 patients • Induced humoral responses to Rosenblatt J et al. Blood. novel antigens (SEREX analysis) 2011;117:393. • Disease stabilization in 70% of patients • DC/MM fusions induce anti-MM immunity in vitro and inhibit MM cell growth in vivo in xenograft models Rosenblatt J et al. Blood. 2011;117:393. Vasir B et al. Br J Haematol. 2005;129:687. Vaccines Targeting MM-Specific Peptides in Smoldering MM • 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. 80 Therapeutic Vaccines in Development Study MM Vaccine Patient Types Phase Sites Dendritic cell fusion vaccine + CT-011 Beth Israel Deaconess Medical Center/ Post-transplant* 2 (monoclonal antibody) 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 Emory/Illinois Cancer Specialists/ Beth Israel Deaconess Medical PVX-410 SMM 1/2 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 Development Study Type Trial Patient Types Phase Site(s) CART-19 for multiple myeloma Relapsed/ refractory 1 University of Pennsylvania Safety study of CAR-modified T cells targeting NKG2D- Relapsed/ refractory 1 Dana-Farber Cancer Institute CAR T ligands Study of T cells targeting B-cell maturation antigen National Cancer Institute Relapsed/ refractory 1 (BCMA) for previously treated multiple myeloma University of Pennsylvania Tadalafil and lenalidomide maintenance with or without Newly diagnosed; Sidney Kimmel Comprehensive activated marrow infiltrating lymphocytes (MILs) in high- relapsed (without 2 Cancer Center risk myeloma prior ASCT) MILs Adoptive immunotherapy with activated marrow- infiltrating lymphocytes and cyclophosphamide graft- Sidney Kimmel Comprehensive versus-host disease prophylaxis in patients with relapse Relapsed/ refractory 1 Cancer Center of hematologic malignancies after allogeneic hematopoietic cell transplantation Affinity- Engineered autologous T cells expressing an affinity- Relapsed/ City of Hope enhanced 1/2 enhanced TCR specific for NY-ESO-1 and LAGE-1 refractory University of Maryland T cells CD3/CD28 activated Id-KLH primed autologous DLI Post-transplant 2 University of Pennsylvania lymphocytes 81 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. 82 CAR-BCMA T Cells in MM: Study Design First-in-human phase 1 trial Pts with advanced RRMM; ≥3 prior lines of therapy; Cyclophosphamide 300 mg/m2 normal organ function; CAR-BCMA T cells* Fludarabine 30 mg/m2 Single infusion clear, uniform BCMA QD for 3 days expression on MM cells (N=12) *Dose escalation of CAR+ T cells/kg 0.3 × 106 1.0 × 106 3.0 × 106 9.0 × 106 • CAR-BCMA expression determined by flow cytometry 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. 83 Bi-Specific Antibody (bsAb) Constructs Antibody Small molecules Bivalent conjugates Tetravalent (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 84 Continuing Evolution of MM Treatment: Selected New Classes and Targets 2016 1st-Generation Novel Agents 2nd-Generation Novel Therapies/ Immunotherapy Atezolizumab* Durvalumab* Lenalidomide Nivolumab* Carfilzomib Ixazomib Pembrolizumab* Thalidomide AC-241/1215* Vaccines* Pomalidomide Daratumumab Bortezomib + CAR-T* Marizomib* Bortezomib Doxil Panobinostat Elotuzumab Isatuximab* 3rd Generation IMiDs* Melflufen* 2003 2006 2007 2012 2013 2015 2016+ IMiD HDAC inhibitor Monoclonal antibody Vaccines Proteasome inhibitor Chemotherapy Adoptive T cell therapy Checkpoint inhibitors *Not yet FDA-approved for MM; available in clinical trials Ongoing MM Collaborative Model for Rapid Translation From Bench to Bedside Pharmaceuticals Advocacy MMRF/C;IMF Academia Progress IMWG; IMS and hope NIH FDA NCI EMEA 19 new FDA-approved drugs/combos/indications in last 13 yrs 85 86