Developments in the Treatment of Multiple Myeloma
Kenneth C. Anderson, M.D.
Kraft Family Professor of MedicineHarvard Medical School
Director, Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute
Conflict of Interest: Kenneth C. Anderson, M.D.
Consultancy: Celgene, Onyx, Sanofi Aventis, and Gilead
Scientific Founder: Acetylon, Oncopep
Integration of Novel Therapy Into Myeloma Management
Bortezomib, Lenalidomide, Thalidomide, Doxil, Carfilzomib, Pomalidamide
Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo
Effective in relapsed/refractory, relapsed MM and now part of induction, consolidation, and maintenance therapy
Nine FDA approvals in the last decade and median survival prolonged from 2-3 yrs to at least 5-7 yrs, with additional prolongation seen from maintenance
New approaches needed to treat and ultimately prevent relapse
Chromosomes and Prognosis in Multiple Myeloma
For conventional low and high dose theapy:
Nonhyperdiploid worse prognosis than hyperdiploid t(11;14), hyperdiplody -standard risk t(4;14), t(14;16),t(14;20), del(17p), del(13q14)-high risk
For novel treatmentsBortezomib, but not lenalidomide, can at least partially overcome t(4;14), del(13q14)-
del(17p) p53 remains high risk
Stewart AK, Richardson PG, San Miguel JF Blood 2009
Combinations in the Upfront Treatment of MM
Lenalidomide and Bortezomib/Lenalidomide-BasedConsolidation
Study details Response data
IFM 2005-021
•Len consolidation (2 mos)•Maintenance randomization: Len vs placebo
IFM 20082
•VRD induction•ASCT•VRD consolidation (2 cycles)•Len maintenance
1Attal et al. Haematologica 2011; 96 (s1): S23; oral presentation at IMW 20112Roussel et al. ASH 2010 (Abstract 624), oral presentation
n=572 Pre-consolidation
Post-consolidation p
CR (IF–) 14% 20% <0.0001
≥ VGPR 58% 67% <0.0001
n=31 Post-induction
Post-ASCT
Post-consolidation
sCR 13% 26% 38%CR 10% 10% 10%≥ VGPR 62% 68% 84%≥PR 94% 91% 94%
5
CALGB 100104:LEN Maintenance significantly prolonged PFS & OS vs. placebo
ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo.
McCarthy PL. N Engl J Med. 2012;366:1770-1781.
PFS OS
• There was significant prolongation of both PFS (HR 0.49, 95% CI, 0.41–0.58, p<0.001) and OS (HR 0.77, 95% CI, 0.62–0.95, p=0.013) with LM vs. placebo/no maintenance
Oral Abstract #407 - Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized TrialsMonday, December 9, 2013: 11:30 AM 393-394
Lenalidomide Maintenance Therapy Meta-Analysis
Singh M, et al. ASH 2013. Abstract 407.
Randomization
NDMM, TE, sge 18–65 y
CAD + GCSF
3 x VAD
CAD + GCSF
3 x PAD
MEL 200 + PBSCT
In GMMG 2nd MEL 200 + PBSCT
MEL 200 + PBSCT
In GMMG 2nd MEL 200 + PBSCT
Thalidomidemaintenance 50 mg/day for 2 years
Allogeneic Tx
Bortezomib Maintenance1.3 mg/m2 / 2 weeks for 2 years
Bortezomib induction and maintenance in ASCT
Bortezomib 1.3 mg/m2i.v.
Doxorubicin 9 mg/m2
Dexameth 40 mg
Sonneveld et al, ASH 2013
Results
• Bortezomib-based treatment consistently improves PFS (median 27 m vs 36 m) and OS (median 84 m vs not reached, p=0.05) in patients with newly diagnosed MM who are transplant eligible
• Bortezomib significantly improves the long-term outcome of patients presenting with renal failure (p<0.001)
Sonneveld et al, ASH 2013
Carfilzomib With Thalidomide and Dexamethasone in ASCT
Induction (4 28-day cycles)
Carfilzomib, 20/27 mg/m2
Days 1,2,8,9,15,16
Dexamethasone, 40 mgDays 1,8,15,21
Thalidomide, 200 mgDays 1-28
Intensification* (1 cycle)
Phase IIopen-labeldose-escalationtrial (N=70)
*High-dose melphalan 200 mg/m2 plus ASCT
Sonneveld P, et al. ASH 2013. Abstract 688.
Carfilzomib, 27 mg/m2
Days 1,2,8,9,15,16
Dexamethasone, 40 mgDays 1,8,15,21
Thalidomide, 50 mgDays 1-28
Consolidation(4 28-day cycles)
Carfilzomib 27 mg/m2 dose escalation: Cohort 1 treatment as above; Cohort 2 to 36 mg/m2; Cohort 3 to 45 mg/m2; Cohort 4 to 56 mg/m2.
Carfilzomib/Thalidomide/ Dexamethasone: Response and AEs
Patient Response, %
High-risk* Patients Standard Risk Patients
All Patients
CR/sCR 57 48 51
≥VGPR 90 76 84
PR 90 90 96
*t(4;14) and/or del(17p) and/or 1q and/or ISS3.
• Grade 3/4 AEs ≥ 5% by carfilzomib dose:• 20/27 mg/m2=GI toxicity, 16%, skin, 12%; metabolism, 10%;
myelotoxicity, 8%; fatigue, 8%; cardiovascular, 6%• 20/36 mg/m2=metabolism, 10%; myelotoxicity, 8%; GI
toxicity, 5%• Neuropathy < 5% in both cohorts
Sonneveld P, et al. ASH 2013. Abstract 688.
Impact of Novel Agents in the Treatment of Elderly Pts with Newly Diagnosed MM
Substantial improvements in PFS and OS
*Median OS not reachedN/A: not available
7San Miguel et al. N Engl J Med 2008; 359(9): 906–917; Supplementary Appendix8Mateos et al. J Clin Oncol 2010; 28(13): 2259-22669Palumbo et al. ASH 2010 (Abstract 622)10Mateos et al. Lancet Oncol 2010; 11(10): 934-94111Palumbo et al. ASH 2010 (Abstract 620)
1Palumbo et al. Blood 2008; 112:3107–31142Facon et al. Lancet 2007; 370:1209–12183Hulin et al. J Clin Oncol 2009; 27:3664-704Waage et al. Blood 2010; 116:1405-125Wijermans et al. J Clin Oncol 2010; 28:3160-66Beksac et al. Eur J Haematol 2011;86:16-22
Median PFS (mos) Median OS (mos)MP1-8 11–20 29.1–49.4MPT1-6 15–27.5 29–51.6VMP7,8,11 21.7–27.4 68.5% (3-yr OS)*MPR-R9 31 N/AVMP-VT/VP10 34 74% (3-yr OS)*VMPT-VT11 37.2 85% (3-yr OS)*
Facon T, et al. Blood. 2013;122:abstract 2.
RA
ND
OM
IZAT
ION
1:1
:1
Arm BRd18
Arm CMPT
LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28
MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN 0.25mg/kg D1-4/42PREDNISONE 2mg/kg D1-4/42THALIDOMIDE 200mg D1-42/42
PD, O
S an
d Su
bseq
uent
ant
i-MM
Tx
PD o
r Una
ccep
tabl
e To
xici
ty
Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4
15
• Stratification: age, country and ISS stage
1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.
FIRST Trial: Study Design
LEN + Lo-DEX ContinuouslyLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28
Arm AContinuous Rd
ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival
Facon T, et al. Blood. 2013;122:abstract 2.
Median PFSRd (n=535)
25.5 mos
Rd18 (n=541)
20.7 mos
MPT (n=547)
21.2 mos
Rd 535 400 319 265 218 168 105 55 19 2 0Rd18 541 391 319 265 167 108 56 30 7 2 0MPT 547 380 304 244 170 116 58 28 6 1 0
Hazard ratio Rd vs. MPT: 0.72; P = 0.00006 Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349
Time (months)
Patie
nts
(%)
100
80
60
40
20
00 6 12 18 24 30 36 42 48 54 60
16
42% (Rd)
23% (Rd18) 23% (MPT)
FIRST Trial: Final Progression-free Survival
mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone.
FIRST Trial: Consistent PFS Benefit Across Subgroups
ITT, intention to treat; ITT comparison for continuous Rd vs. MPT
Facon T, et al. Blood. 2013;122:abstract 2.
SubgroupAge > 75Age ≤ 75
Gender: femaleGender: male
AsiaEurope
North America and PacificISS stage: I or II
ISS stage: IIICrCI < 30 ml/min
CrCI 30 – 50 ml/minCrCI 50 – 80 ml/min
CrCI ≥ 80 ml/minECOG PS Grade 0ECOG PS Grade 1ECOG PS Grade 2
LDH < 200 IU/lLDH ≥ 200 IU/l
Cytogenetics High-risk Cytogenetics Non-high Risk
ITT patients
Hazard ratio (HR) and 95% CI HR (95% Cl)0.81 (0.62 - 1.05)0.68 (0.56 - 0.83)0.73 (0.58 - 0.93)0.71 (0.57 -0.88)0.61 (0.33 - 1.14)0.77 (0.63 - 0.93)0.64 (0.46 - 0.89)0.70 (0.57 - 0.87)0.75 (0.59 - 0.95)0.76 (0.44 - 1.30)0.66 (0.48 - 0.91)0.74 (0.58 - 0.95)0.71 (0.51 - 1.01)0.54 (0.39 - 0.74)0.81 (0.65 - 1.01)0.80 (0.57 - 1.12)0.69 (0.58 - 0.83)0.96 (0.66 - 1.39)1.23 (0.78 - 1.93)0.69 (0.53 - 0.90)
0.72 (0.61 - 0.85)
0.125 0. 25 0.5 1 2 4 8
Favoring MPTFavoring Rd
17
Cytogenetics high-risk included t(4;14), t(14;16), del(17p)
FIRST Trial: TTP and Time to 2nd Anti-myeloma Therapy
Facon T, et al. Blood. 2013;122:abstract 2.
RdRd18MPT
535541547
398389379
318317303
263265242
218167169
167108115
1055658
553028
1976
221
000
TTP (months)
Patie
nts
(%)
100
80
60
40
20
00 6 12 18 24 30 36 42 48 54 60
Hazard ratio Rd vs. MPT: 0.68; P=0.00001 Rd vs. Rd18: 0.62; P≤0.00001 Rd18 vs. MPT: 1.11; P=0.21718
Time to Progression Time to 2nd AMT
RdRd18MPT
535541547
445451422
371375351
319331293
275266239
224181177
142111101
776142
28169
321
000
Time to 2nd AMT (months)
100
80
60
40
20
0
Hazard ratioRd vs. MPT: 0.66; P<0.00001Rd vs. Rd18: 0.74; P=0.00067Rd18 vs. MPT: 0.88; P=0.12333
0 6 12 18 24 30 36 42 48 54 60
Patie
nts
(%)
Median TTP
Rd (n=535)
32.5 mos
Rd18 (n=541)
21.9 mos
MPT (n=547)
23.9 mos
Median Time to 2nd AMT
Rd (n=535)
39.1 mos
Rd18 (n=541)
28.5 mos
MPT (n=547)
26.7 mos
18
FIRST Trial: Conclusions• Continuous Rd significantly extended PFS, with an OS benefit vs. MPT
– PFS: • HR= 0.72 (P= 0.00006)• Consistent benefit across most subgroups• Rd better than Rd18 (HR= 0.70, P= 0.00001)• 3 yr PFS: 42% Rd vs. 23% Rd18 and MPT
– Planned interim OS: HR= 0.78 (P= 0.0168)– Rd was superior to MPT across all other efficacy secondary endpoints
• Safety profile with continuous Rd was manageable – Hematological and non-hematological AEs were as expected for Rd and
MPT– Incidence of hematological SPM was lower with continuous Rd vs. MPT
• In NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care
Facon T, et al. Blood. 2013;122:abstract 2.
19
20
0
HR, hazard ratio; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; OS, overall survival; PFS, progression-free survival; TTP, time to progression.
ProgressionProgression--Free and Overall SurvivalFree and Overall SurvivalAll PatientsAll Patients
• TTP HR advantages were similar: MPR-R vs MP = 0.337; MPR vs MP = 0.826
Time (Months)
Patie
nts
(%)
HR 0.395 P < .001
HR 0.796P = .135
0 10 20 30 400
25
50
75
100
Median PFS
MPR-R 31 monthsMPR 14 monthsMP 13 months
Median PFS
MPR-R 31 monthsMPR 14 monthsMP 13 months
0 20 30 40 50 60
4-year OSMPR-R 59%MPR 58%MP 58%
4-year OSMPR-R 59%MPR 58%MP 58%
Patie
nts
(%)
25
50
75
10
100
HR 0.898 P = .579
HR 1.089P = .648
Time (Months)
21
Second Primary MalignanciesSecond Primary MalignanciesAll PatientsAll Patients
SPM, n (IR per 100 per year) MPR-R(n = 150)
MPR(n = 152)
MP(n = 153)
Total Invasive SPMs 12 (3.04) 10 (2.57) 4 (0.98)Hematologic 7 (1.75) 6 (1.54) 1 (0.24)Solid tumors 5 (1.26) 5 (1.28) 3 (0.74)
Non-melanoma skin cancer 2 (0.50) 5 (1.29) 6 (1.50)
SPM, n (IR per 100 per year) MPR-R(n = 150)
MPR(n = 152)
MP(n = 153)
Total Invasive SPMs 12 (3.04) 10 (2.57) 4 (0.98)Hematologic 7 (1.75) 6 (1.54) 1 (0.24)Solid tumors 5 (1.26) 5 (1.28) 3 (0.74)
Non-melanoma skin cancer 2 (0.50) 5 (1.29) 6 (1.50)
Patie
nts
(%)
100
75
50
25
0
100
75
50
25
0
100
75
50
25
00 20 40 60 0 20 40 60 0 20 40 60
Time (Months) Time (Months) Time (Months)
MPR-R MPR MPPD/Death Hematologic SPM Solid TumorPD/Death Hematologic SPM Solid Tumor
IR, incidence rate; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; PD, progressive disease; PY, person-year; SPM, second primary malignancy.
Treatment schema
VPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22P: 50 mg, 3 times wk
VCPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22C: 50 mg, 3 times wkP: 50 mg, 3 times wk
MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15
VMPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22M: 2 mg, 3 times wkP: 50 mg, 3 times wk
MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15
MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15
VPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22P: 50 mg, 3 times wk
VCPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22C: 50 mg, 3 times wkP: 50 mg, 3 times wk
MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15
VMPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22M: 2 mg, 3 times wkP: 50 mg, 3 times wk
MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15
MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15
Vsc, subcutaneous bortezomib; C, cyclophosphamide; M, melphalan; P, prednisone
152 patients
≥ 75 years or younger with co-morbidities
At baseline: geriatric assessment (ADL, IADL, Charlson)
Larocca et al ASH 2013
Subgroup analysis: AgePa
tient
s(%
)
OS, Age 75-80 vs Age<75, HR=0.79 p=0.571OS, Age 80 vs Age<75, HR=0.99 p=0.990
Progression-free Survival Overall Survival
PFS, Age 75-80 vs Age<75, HR=0.96 p=0.865PFS, Age 80 vs Age<75, HR=0.80 p=0.449
0
25
50
75
100
0 6 12 18 24 30Time (months)
Age 75-80 yearsAge <75 yearsAge 80 years
0
25
50
75
100
0 6 12 18 24 30Time (months)
Age 75-80 yearsAge <75 yearsAge 80 years
Time (months)
0
25
50
75
100
0 6 12 18 24 30
Age 75-80 yearsAge <75 yearsAge 80 years
0
25
50
75
100
0 6 12 18 24 30
Age 75-80 yearsAge <75 yearsAge 80 years
Conclusions
• The global population is rapidly aging. Aging is associated with an increased incidence of co-morbidity, frailty, and disability.
• PFS and OS appeared similar between the 2- drug and the 3-drug combinations
• Melphalan seemed more toxic than cyclophosphamide
• Fit patients
Unfit patients
Frail patients
Full dose therapy
Reduced-dose therapy
Further reduced-dose therapy
Larocca et al, ASH 2013
• Phase II• Multicenter (10 centres)
Study design
CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5
Dexamethasone40 mg orally
Cyphosphamide300 mg/m2 orally
CarfilzomibDose (mg/m2)
Dosing
Cycle day 1 2 15 16 1 2 8 9 1516 22
20 36 36 36 36 361 2 8 9 1516 22 1 2 8 9 1516 22
CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE
36 36 361 2 15 16 1 2 15 16
36 36 36 3636 36
Response Assessments
CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5
Dexamethasone40 mg orally
Cyphosphamide300 mg/m2 orally
CarfilzomibDose (mg/m2)
Dosing
Cycle day 1 2 15 16 1 2 8 9 1516 22
20 36 36 36 36 361 2 8 9 1516 22 1 2 8 9 1516 22
CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE
36 36 361 2 15 16 1 2 15 16
36 36 36 3636 36
Response Assessments
CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5
Dexamethasone40 mg orally
Cyphosphamide300 mg/m2 orally
CarfilzomibDose (mg/m2)
Dosing
Cycle day 1 2 15 16 1 2 8 9 1516 22
20 36 36 36 36 361 2 8 9 1516 22 1 2 8 9 1516 22
CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCECYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE
36 36 361 2 15 16 1 2 15 16
36 36 36 3636 36
Response Assessments
CCd Induction C MaintenanceCycles 1-9 Until progression
CCd Induction C MaintenanceCycles 1-9 Until progression
Bringhen et al ASH 2013
Conclusions 1
CCd MPT VMP RdResponse rates≥ VGPR 77% 36% 41% 40%nCR/CR/sCR 47% 27% 30%* 14%Long-term outcomes2-yr PFS 76% 47% ~47% ~47%2-yr OS 87% 76% 79% 87%
CCd MPT VMP RdResponse rates≥ VGPR 77% 36% 41% 40%nCR/CR/sCR 47% 27% 30%* 14%Long-term outcomes2-yr PFS 76% 47% ~47% ~47%2-yr OS 87% 76% 79% 87%
* CR only, nCR not reported
Palumbo at al, Lancet, 2006 ;367:825-31.Fayers et al, Blood 2011; 118:1239-47; San Miguel et al, N Eng J Med 2008;359:906-17; Rajkumar et al, Lancet Oncol 2010; 11:29-37
Bringhen et al ASH 2013
Oral MLN 9708 Len Dex in Newly Diagnosed MM
• Phase 1: oral MLN9708 dose-escalation (dose of 3.0 and 3.7 mgs)– Standard 3+3 schema, 33% dose increments, based on cycle 1 DLTs
• Phase 2: oral MLN9708 at the RP2D from phase 1• Stem cell collection allowed after cycle 4, with ASCT deferred until after 8
cycles• MLN9708 maintenance continued at tolerated dose until progression or
unacceptable toxicity
1 8 15 21
MLN9708 maintenance
Days 1, 4, 8, 1121-day cycles
Induction: up to 16 x 21-day treatment cycles Maintenance
MLN9708 MLN9708 MLN9708
Dex* Dex* Dex*
Lenalidomide 25 mg, days 1–14
MLN9708
Dex*
4 11
*Dex 20/10 mg cycles 1–8 / 9–16Thromboembolism prophylaxis with aspirin 81–325 mg QD or LMWH while receiving len-dex mandatory
2 5 9 12
Richardson et al ASH 2013
Ixazomib lenalidomide dexamethasone in newly diagnosed multiple myeloma
• 56 pts treated at the RP2D were evaluable for response (7 phase 1, 49 phase 2)
• 61% of pts had 100% decreases in M-protein or serum free light chain from baseline
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
0
–20
–40
–60
–80
–100
% d
ecre
ases
in M
-pro
tein
–25%
–50%
–90%
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56
Subject identifier for the study
Dose level (cohort): Ph 1, 3.0 mg Ph 2, 3.0 mg
Richardson et al ASH 2013
Pomalidomide With Low-Dose Dexamethasone Relapsed and Refractory Multiple Myeloma
• POM was effective in heavily pretreated patients who had already received LEN and bortezomib and who progressed on their last line of therapy
• The combination of POM with LoDEX improves the ORR due to synergy between immunomodulatory agents and glucocorticoids
POM + LoDEX, 34%; POM alone, 15%
• Response was durable with POM regardless of the addition of LoDEX
POM + LoDEX, 8.3 months ; POM alone, 8.8 months
• POM is generally well tolerated, with low rates of discontinuations due to AEs
• Age had no impact on ORR, DoR, or safety
Jagannath S, et al. ASH 2012 abstract 450.
MM-003 Design: POM + LoDEX vs. HiDEX
(n = 302)POM: 4 mg/day D1-21 +LoDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22
RA
ND
OM
IZAT
ION
2:1
Follow-Up for OS and SPM
Until 5 Years Post Enrollment
(n = 153)HiDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1-4, 9-12, 17-20
28-day cycles
PDa or
Unacceptable AE
Companion trialMM-003C
POM 21/28 days
Stratification• Age (≤ 75 vs. > 75 yrs)• Number of prior Tx ( 2 vs. > 2)• Disease population (primary refractory vs. relapsed/refractory vs. intolerance/failure)
Thromboprophylaxis was required for those receiving POM or at high risk for DVT
PDa or
Unacceptable AE
a Progression of disease was independently adjudicated in real time.
Dimopoulos MA, et al. ASH 2013 [abstract 408].
0.25 0.5
PFS Based on Cytogenetic Profile• POM + LoDEX significantly improved PFS vs. HiDEX regardless of the
presence of del17p or t(4;14)
Note: Data shown only for pts with available cytogenetics; totals will not sum.a Number of events/number of patients.Dimopoulos MA, et al. ASH 2013 [abstract 408].
ITT Population
del(17p)/t(4;14)
Standard-RiskCytogenetics
Subgroup POM + LoDEXa HiDEXa HR (95% CI)
0.49 (0.40-0.61)
0.44 (0.28-0.68)
0.55 (0.40-0.75)
138/153
32/35
63/72
253/302
71/77
126/148
1
Favors POM + LoDEX
2
Favors HiDEX
Forest Plot of OS Based on Prior Treatment
a Number of events/number of pts.
San Miguel JF, et al. ASH 2013 [abstract 686].
Subgroup HiDEXa HR (95% CI)
0.72 (0.56-0.92)
0.56 (0.33-0.96)
0.76 (0.58-1.00)
0.75 (0.55-1.03)
0.66 (0.45-0.99)
0.70 (0.55-0.90)
0.77 (0.58-1.01)
0.77 (0.58-1.02)
0.56 (0.36-0.88)
0.92 (0.63-1.36)
101/153
22/33
79/120
64/93
37/60
94/141
79/121
74/113
32/49
39/66
176/302
41/70
135/232
102/173
74/129
168/286
142/238
135/225
47/85
76/134
ITT Population
≤ 3 Prior Tx
> 3 Prior Tx
Prior THAL
No Prior THAL
LEN Ref
BORT Ref
LEN and BORT Ref
LEN as Last Prior
BORT as Last Prior
POM + LoDEXa
0.25 0.5 1 2
Favoring POM-LoDex Favoring HiDEX
MM-003: PFS and OS by M-Protein ReductionPatients Assigned to POM + LoDEX
San Miguel JF, et al. ASH 2013 [abstract 686].
• Median PFS was 4.0 mos and median OS was 13.1 mos overall for POM + LoDEX
M-Protein Reduction
Median PFS
≥ 25 % (n = 163) 7.4 mos
≥ 50 % (n = 113) 8.4 mos
< 25% (n = 96) 2.3 mos
M-Protein Reduction
Median OS
≥ 25 % (n = 163) 17.2 mos
≥ 50 % (n = 113) 19.9 mos
< 25% (n = 96) 7.5 mos
PFS (mos)
0.0
0.2
0.4
0.6
0.8
1.0
4 8 12 16 20 240
Prop
ortio
n of
Pat
ient
s
OS (mos)
0.0
0.2
0.4
0.6
0.8
1.0
4 8 12 16 20 280 24
Pom low dose dex and bortezomib in relapsed MM
Table 4. Summary of Best Response (IMWG) in Intravenous BORT Cohorts
Outcome Cohort 1(n = 3)
Cohort 2(n = 3)
Cohort 3(n = 3)
Cohort 4(n = 3)
Cohort 5 + Exp Cohort
(n = 9)a
Overall response, n (%) 2 (67) 1 (33) 3 (100) 3 (100) 6 (67)
sCR/CR 0 0 0 0 1 (11)
VGPR 1 (33) 0 2 (67) 1 (33) 4 (44)
PR 1 (33) 1 (33) 1 (33) 2 (67) 1 (11)
SD 1 (33) 2 (67) 0 0 3 (33)
Median cycles received (range) 5 (4-16) 6 (4-18) 16 (5-20) 10 (4-13) 11 (6-15)
a 8 of 9 patients were evaluable for response; one patient discontinued study treatment in cycle 2 due to treatment-unrelated metastatic pancreatic cancer. CR, complete response; Exp, expansion; IMWG, International Myeloma Working Group; PR, partial response; SC, subcutaneous; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.
Richardson et al, ASH 2013
Carfilzomib: A Novel Proteasome (Chymotryptic) Inhibitor
• Novel chemical class with highly selective and irreversible proteasome binding
• Improved antitumor activity with consecutive day dosing
• No neurotoxicity in animals
• 23% Responses lasting 7.8 months with survival 15.4 months in relapsed and relapsed/ refractory MM w/o
Demo et al Cancer Res 2007; 67:6383 Kirk et al, Blood 2008, 112: 2765 ; Siegel et al Blood 2012:120:2817.
HN
NH
O HN
O
O
NHO
NO O
O
Epoxyketone
Tetrapeptide
CRd in Relapsed and Upfront MM
• Response to CRd therapy in RRMM was high, with an ORR of 78%
41% VGPR or better
• CRd well-tolerated with durable responses
• ASPIRE phase 3 open-label, international, multicenter trial comparing CRd to Rd in R/R MM fully enrolled.
• Remarkable extent and frequency of response to CRd upfront in ND MM (94% ORR, with 80% CR,nCR after 12 cycles in a subset of pts)
Wang et al ASCO 2011; Jakubowiak et al, Blood 2012
Carfilzomib Pomalidomide Low dose Dex
• Median of 5 prior lines of therapy; 49% of patients had high/intermediate risk cytogenetics at baseline
• Response rates, PFS, and OS were preserved independent of FISH/cytogenetic risk status
• Well tolerated with no unexpected toxicities
≥ VGPR 27% ORR 70% CBR 83% DOR (median) 17.7
months PFS (median) 9.7 months OS (median) > 18
months
Shah et al ASH 2013
Antibody-dependentCellular cytotoxicity
(ADCC)
ADCC
Effector cells:
MM
FcR
Complement-dependentCytotoxicity (CDC)
CDC
MM
C1q
C1q
Apoptosis/growth arrest
via targetingsignaling pathways
MM
Lucatumumab or Dacetuzumab (CD40)Elotuzumab (CS1)Daratumumab (CD38)XmAb5592 (HM1.24)
huN901-DM1 (CD56)nBT062-maytansinoid
(CD138)1339 (IL-6)BHQ880 (DKK1)RAP-011 (activin A)Daratumumab (CD38)
Daratumumab (CD38)
MAb-Based Therapeutic Targeting of Myeloma
Tai & Anderson Bone Marrow Research 2011
• CS1 is highly and uniformly expressed on MM cells • Elotuzumab (Elo) is a humanized monoclonal IgG1
antibody targeting CS1 • Clinical trial of Elo in MM achieved SD • Anti-MM activity of Elo enhanced by lenalidomide (len)
in preclinical models• Phase I/II trials: 80-90% response to len dex elo in
relapsed MM with prolonged (> month 33 PFS)• Phase III trial of len dex elo versus len dex in relapsed
MM for new drug approval
Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784; Tai YT et al. Blood. 2008;112:1329-1337; Van Rhee F et al. Mol Cancer Ther. 2009;8:2616-2624; Lonial S et al. Blood. 2009;114:432; Richardson et al Blood 2010:864 Lonial et al, ASH 2012
Elotuzumab Anti-CS MoAb in MM
Martin et al ASH 2013
Martin et al 2013
PHASE I/II STUDY OF DARATUMUMAB CD38 MONOCLONAL ANTIBODY IN
RELAPSED/REFRACTORY MM • Favorable safety profile as monotherapy
• In 15 of 32 (47%) showed benefit
– 4 patients achieving PR (13%)– 6 patients achieving MR (19%)– 5 patients achieving SD (16%)
• At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%)
• To be combined with lenalidomide dexamethasone
Plesner et al ASH 2012
44
Daratumumab and lenalidomide dexamethasone in relapsed MM
The best change in response paraprotein evaluated according to IMWG 2011.
A: serum M-protein, B: urine-M-proteinPlesner et al ASH 2013
Kelley et al ASH 2013
Kelly et al ASH 2013
Background: Targeting KSP with ARRY-520 (Filanesib)
• Filanesib is a targeted Kinesin Spindle Protein (KSP) inhibitor
– KSP is a microtubule motor protein critical to the function of proliferating cells
• KSP inhibition induces aberrant mitotic arrest and rapid cell death
– Novel mechanism of action for MM– Preferentially acts on MCL-1
dependent cells including MM– Not expected to be cross-resistant
with other drugs
47Lonial et al ASH 2013
Low AAG is Associated with Higher ORR
48
1 5 patients did not have a baseline AAG measurement2 4 patients did not have a baseline AAG measurement, including 1 responder
Filanesib Single-agent Filanesib + Dex
All Pts1 AAG-High AAG-Low All Pts2 AAG-High AAG-Low
n 32 6 21 55 15 36
ORR (≥ PR) 5 (16%) 0 (0%) 5 (24%) 8 (15%) 0 (0%) 7 (19%)
CBR (≥ MR) 7 (22%) 0 (0%) 7 (33%) 11 (20%) 0 (0%) 10 (28%)
Duration of Response (months) 8.6 - 8.6 5.1 - 5.1
Time to Next Treatment (months) 3.7 2.6 5.3 3.4 2.0 5.1
OS (months) 19.0 4.5 23.3 10.5 2.9 10.8
Lonial et al ASH 2013
Protein
protein aggregates(toxic)
UbUb
UbUb
26S proteasome
UbUb
Ub UbUb
Aggresome
Panibinostat,Vorinostat, ACY1215
dynein
UbUb
dynein
MicrotubuleAutophagy
Bortezomib, Carfilzomib, NPI0052, MLN9708, ONX 0912
Ub UbUb
Lysosome
HDAC6
HDAC6
HDAC6
Ub
Ub
Development of Rationally-Based Combination Therapies (HDAC and Proteasome Inhibitors)
Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:3441-9.
VANTAGE 088: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat
or Placebo with Bortezomib in Relapsed MM• The combination of vorinostat + bortezomib is active in patients
with relapsed and refractory MM– Significant improvement in response rate– ORR 54% vs 41% (P<0.0001); CBR 71% vs 53% (P<0.0001)
• PFS and TTP were prolonged in the combination arm compared with bortezomib alone
PFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4)versus 6.83 months (5.7–7.7)
• Diarrhea, fatigue, and thrombocytopenia limited tolerability.
Dimopoulos et al Lancet Oncol 2013; 14: 1129-40.
Ricolinostat (HDAC 6 inhibitor) alone and in combination with bortezomib in relapsed
refractory MM• Monotherapy
• 6/15 patients had stable disease (SD) as their best response. • Combination with bortezomib and dexamethasone
• 20/22 were evaluable for response assessment in six combination cohorts
• Overall response rate (≥PR): 25% in heavily pretreated patients• 5 patients withdrew after one cycle and 3 had progressive disease after 2
cycles• Clinical benefit rate (≥SD): 60%• 6/10 patients refractory to bortezomib had ≥SD (1 VGPR, 1 MR, 4 SD)• Responding patients have been on study 2 to 16 cycles• All 3 patients treated 240 mg QD cohort had MR or better
VGPR 2
PR 3
MR1 2
SD 5
Monotherapy response data from Final CSR. Combination response data pulled from live database Nov 8, 2013
51
1 One patient had a 26% decrease in M Protein after Cycle 2 and withdrew after two subsequent cycles with SD
Ricolinostat (HDAC 6 inhibitor) lenalidomide dexamethasone in relapsed refractory MM
• 11/16 pts (69%) had PR or better• 16/16 pts (100%) had clinical benefit (including MR and SD)
CR 1VGPR 3PR1 7MR 2SD 3
Yee, et al, Poster #3190, ASH 201352
M protein % change
PKB115125 Akt Inhibitor: Dose Limiting Toxicities
Afur / Bor / Dex dose (mg)
n DLT Comment
75- 1.0- 20 4 None -
100 - 1.3- 20 6 1/6 LFT elevation G2
125 - 1.3- 20 6 1/6 Erythema Multiforme G3
150 - 1.3- 20 6 None -
175 - 1.3- 20 6 2/6 Rash G3Rash G3 / Diarrhea G3 /Thrombocytopenia G3
150 -1.3- 40 6 NA -
MTD / RP2D:Afuresertib 150 mg PO dailyBortezomib 1.3 mg/m2 IV/SC on days: 1,4,8,11Dexamethasone 40 mg PO on days: 1,4,8,11
All DLTs were reversible
Voorhees et al ASH 2013
Maximum % change in M-protein or FLC from baseline
Voorhees et al ASH 2013
Treatment of Multiple Myeloma: Conclusions
• In newly diagnosed transplant candidates, three drug regimens incorporating immunomodulatory drugs and proteasome inhibitors before and after transplant can prolong PFS and OS.
• Lenalidomide dex until progression is standard of care for non transplant patients with newly diagnosed myeloma.
• Lenalidomide maintenance until progression prolongs PFS and OS, with an increased risk of secondary cancers in patients who have received MP or high dose therapy and ASCT.
Treatment of Multiple Myeloma: Conclusions
• Pomalidomide low dose dex is active in relapsed refractory MM, (including 17p deletion)
• Bortezomib or Carfilzomib and pomalidomide low dose dex increases response and is tolerated in relapsed refractory MM
• Novel agents including oral proteasome inhibitor ixazomib, monoclonal antibodies SAR650984 and daratumumab, immunotoxin indatuximab, KSP inhibitor filanesib, Akt inhibitor afuresertib, and HDAC6 inhibitor ricolinostat demonstrate promising activity in relapsed refractory MM
• Incorporation of novel therapies at all stages of disease is further improving patient outcome in MM
