1. December 7-10, 2013 New Orleans, Louisiana
Updates in Multiple Myeloma CCO Independent Conference Coverage of the 2013 Annual Meeting of the American Society of Hematology*
December 7-10, 2013
New Orleans, Louisiana
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC
This program is supported by educational grants from
This program is supported by an educational grant from

2. Active treatment + PFS follow-up phase PD or unacceptable toxicity
FIRST: Lenalidomide/Dexamethasone vs MPT in NDMM SCT-Ineligible Patients[1]
Active treatment + PFS follow-up phase
Phase III
N = 1623
Randomization 1:1:1
Arm A
Continuous Rd
Len + LoDex Continuously
Lenalidomide 25 mg Days 1-21/28
LoDex 40 mg Days 1, 8, 15, 22/28
PD or unacceptable toxicity
subsequent anti-MM Tx
PD, OS, and
Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28
LoDex mg Days 1, 8, 15, 22/28
Arm B
Rd18
ISS, International Staging System; Len, lenalidomide; LoDex, low-dose dexamethasone; Mel, melphalan; MM, multiple myeloma; MPT, melphalan/prednisone/thalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Pred, prednisone; Rd, lenalidomide/low-dose dexamethasone; SCT, stem-cell transplantation; Thal, thalidomide; Tx, treatment.
Mel + Pred + Thal 12 cycles[2] (72 wks)
Melphalan 0.25 mg/kg Days 1-4/42
Prednisone mg/kg Days 1-4/42
Thalidomide mg Days 1-42/42
Arm C
MPT
Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal[3] 100 mg Days 1-42/42; Mel[3] 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage.
1. Facon T, et al. ASH Abstract Facon T, et al. Lancet. 2007;370: Hulin C, et al. J Clin Oncol. 2009;27:

3. FIRST Trial: Progression-Free Survival
100 80 60 40 20
Median PFS
Rd (n = 535)
25.5 mos
Rd18 (n = 541)
20.7 mos
MPT (n = 547)
21.2 mos
HR:
Rd vs MPT: 0.72 (P = )
Rd vs Rd18: 0.70 (P = )
Rd18 vs MPT: 1.03 (P = )
Patients (%)
MPT, melphalan/prednisone/thalidomide; PFS, progression-free survival; Rd, lenalidomide/low-dose dexamethasone.
72 wks 6 12 18 24 30 36 42 48 54 60
Mos
1. Facon T, et al. ASH Abstract 2. Reproduced with permission.

4. MPR or CPR vs Lenalidomide/LoDex in Elderly Patients With NDMM
1st randomization
2nd randomization
Rd (n = 220), 9 28-day courses
R: 25 mg Days 1-21
d: 40 mg Days 1,8,15,22
R maintenance
28-day cycle until relapse
R: 10 mg/day Days 1-21
Phase II trial:
transplant-
ineligible pts with NDMM
(N = 660)
MPR (n = 217), 9 28-day courses
M: 0.18 mg/kg Days 1-4
P: 1.5 mg/kg Days 1-4
R: 10 mg Days 1-21
PR maintenance
28-day cycle until relapse
P: 25 mg 3 x wk
R: 10 mg/day Days 1-21
C, cyclophosphamide; CPR, cyclophosphamide/prednisone/lenalidomide; d, low-dose dexamethasone; LoDex, low-dose dexamethasone; M, melphalan; MPR, melphalan/prednisone/lenalidomide; NDMM, newly diagnosed multiple myeloma; P, prednisone; QOD, every other day; R, lenalidomide; Rd, lenalidomide/low-dose dexamethasone.
CPR (n = 222), 9 28-day courses
C: 50 mg Days 1-21
P: 25 mg 3 x wk
R: 25 mg Days 1-21
Dose adjustments for patients > 75 yrs of age: dexamethasone 20 mg/wk; melphalan 0.13 mg/kg; cyclophosphamide 50 mg QOD on days 1-21.
12. Palumbo A, et al. ASH Abstract 536.

5. CPR vs MPR vs Rd Survival Outcome: PFS and OS
Median follow-up 26 mos
PFS OS
0.25
0.50
0.75
1.00
0.25
0.50
0.75
1.00
Median PFS
CPR
24 mos
MPR
27 mos Rd
22 mos
2-Yr OS
CPR
84%
MPR
81% Rd
80%
Patients (%)
CPR, cyclophosphamide/prednisone/lenalidomide; MPR, melphalan/prednisone/lenalidomide; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide, low-dose dexamethasone.
Rd vs MPR: HR: 1.189; Cl: ; P = .20
Rd vs CPR: HR: 1.032; Cl: ; P = .81
Rd vs MPR: HR: 0.954; Cl: ; P = .82
Rd vs CPR: HR: 1.033; Cl: ; P = .88 10 20 30 40 50 10 20 30 40 50
Mos
Mos
12. Palumbo A, et al. ASH Abstract 536. Reproduced with permission.

6. Carfilzomib With Thalidomide and Dexamethasone
Intensification* (1 cycle)
Induction (Four 28-day cycles)
Consolidation (Four 28-day cycles)
Carfilzomib 20/27 mg/m2
Days 1, 2, 8, 9, 15, 16
Carfilzomib 27 mg/m2
Days 1, 2, 8, 9, 15, 16
Phase II open-label
dose-escalation
trial (N = 70)
Thalidomide 200 mg
Days 1-28
Thalidomide 50 mg
Days 1-28
ASCT, autologous stem cell transplantation.
Dexamethasone 40 mg
Days 1, 8, 15, 21
Dexamethasone 40 mg
Days 1, 8, 15, 21
*High-dose melphalan 200 mg/m2 plus ASCT.
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
14. Sonneveld P, et al. ASH Abstract 688.

7. Carfilzomib/Thalidomide/Dexamethasone: Response and AEs
Patient Response, %
High-Risk* Patients (n = 30)
Standard-Risk Patients (n = 25)
All Patients
(N = 70)
CR/sCR 57 48 51
≥ VGPR 90 76 84 PR 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
AEs, adverse events; CR, complete response; GI, gastrointestinal; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
14. Sonneveld P, et al. ASH Abstract 688. Reproduced with permission.

8. Progression-Free Survival and Overall Survival, PAD vs VAD
PFS, Censored at Allo SCT OS
100
100 75 75
PAD
PAD
Cumulative Percentage 50
VAD 50
Cumulative Percentage
VAD N F N D 25 25
VAD
414
311
VAD
414
182
Allo SCT, allogeneic stem-cell transplant; D, number of patients who died; F, number of patients who progressed; LR, log-rank; N, number of patients in study arm; OS, overall survival; PAD, bortezomib/doxorubicin/dexamethasone; PFS, progression-free survival; VAD, vincristine/doxorubicin/dexamethasone.
PAD
413
284
PAD
413
155
Cox LR stratified P = .002
Cox LR stratified P = .05 12 24 36 48 60 72 84 12 24 36 48 60 72 84
Mos
Mos
Pts at Risk, n
VAD
414
292
202
143
100 59 30 10
PAD
413
326
240
170
122 82 45 17
Pts at Risk, n
VAD
414
361
327
278
249
182 79 20
PAD
413
375
343
307
271
193
101 28
HR: 0.76 (95% CI: ; P = .001)
HR: 0.78 (95% CI: ; P = .01)
20. Sonneveld P, et al. ASH Abstract 404. Reproduced with permission.

9. Survival of Patients With Renal Failure, PAD vs VAD
PFS OS
N D
VAD, BLC <
VAD, BLC >
PAD, BLC <
PAD, BLC >
N F
VAD, BLC <
VAD, BLC >
PAD, BLC <
PAD, BLC >
100
100 75 75
Cumulative Percentage 50
Cumulative Percentage 50
BLC, baseline creatinine level; D, number of patients who died; F, number of patients who progressed; N, number of patients in study arm; OS, overall survival; PAD, bortezomib/doxorubicin/dexamethasone; PFS, progression-free survival; VAD, vincristine/doxorubicin/dexamethasone. 25 25 12 24 36 48 60 72 84 12 24 36 48 60 72 84
Mos
Mos
20. Sonneveld P, et al. ASH Abstract 404. Reproduced with permission.

10. Ixazomib in Combination With Lenalidomide and Dexamethasone1 8 15 21
Induction: up to 16 21-day treatment cycles
Ixazomib*
Ixazomib
Dex†
Dex
Lenalidomide 25 mg, Days 1-14 4 11 2 5 9 12
*Dose escalation, 3.0 or 3.7 mg
†20/10 mg cycles 1-8/9-16
Maintenance
Ixazomib
maintenance
Days 1, 4, 8, 11
21-day cycles
ASCT, autologous stem-cell transplantation; Dex, dexamethasone; DLT, dose-limiting toxicity; LMWH, low–molecular-weight heparin; QD, every day; Rd, lenalidomide/low-dose dexamethasone; RP2D, recommended phase II dose; VTE, venous thromboembolism.
Phase I: standard schema, 33% dose increments, based on cycle 1 DLTs
Phase II: treatment at the RP2D established for ixazomib in phase I (3.0 mg)
VTE prophylaxis with aspirin mg QD or LMWH while receiving Rd
Stem cell collection allowed after cycle 4, with ASCT deferred until after 8 cycles
27. Richardson PG, et al. ASH Abstract 535.

11. Ixazomib Plus RD: ORR Over Course of Treatment
100 80 60 40 20
93%
95%
95% 9 16 2 21 7 6 50 48
Patients (%) 48
CR, complete response; DOR, duration of response; ORR, overall response rate; PR, partial response; RD, lenalidomide/dexamethasone; sCR, stringent complete response; VGPR, very good partial response. 32 24 20
After 4 Cycles
After 8 Cycles
Overall (N = 56)
Median DOR 13.8 mos, ranging up to mos
PR VGPR CR sCR
27. Richardson PG, et al. ASH Abstract 535. Reproduced with permission.

12. Summary: Treatment for Patients With Newly Diagnosed Multiple Myeloma
In phase 3 results from FIRST trial, Rd therapy superior to MPT for PFS and OS with similar safety profiles
In elderly patients, similar efficacy seen with MPR, CPR, and Rd treatment; MPR AEs worse than CPR and Rd
Bortezomib-based treatment significantly improved PFS and OS in transplant-eligible NDMM patients vs VAD
Lenalidomide-based maintenance therapy showed significantly higher PFS vs no maintenance or placebo, but greater risk of grade 3/4 neutropenia, VTE, thrombocytopenia, fatigue, and secondary malignancies
Twice-wkly oral ixazomib plus lenalidomide/dexamethasone active in patients with NDMM
AEs, adverse events; CPR, cyclophosphamide/prednisone/lenalidomide; MPR, melphalan/prednisone/lenalidomide; MPT, melphalan/prednisone/thalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide/low-dose dexamethasone; VAD, vincristine/doxorubicin/dexamethasone; VTE, venous thromboembolism.

13. MM-003 Final Analysis: Pomalidomide/ LoDex vs HiDex: PFS and OS
Median PFS, Mos
POM + LoDex (n = 302)
4.0
HiDex† (n = 153)
1.9
Median OS, Mos
POM + LoDex (n = 302)
13.1
HiDex† (n = 153)
8.1
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
HR: 0.72
P = .009
HR: 0.50
P < .001
Proportion of Patients
Proportion of Patients
HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; OS, overall survival; PFS, progression-free survival; POM, pomalidomide.
PFS (Mos)
OS (Mos)
*Primary endpoint. †85 pts (56%) on the HiDex arm received subsequent POM.
36. Dimopoulos MA, et al. ASH Abstract 408. Reproduced with permission.

14. MM-003: PFS Based on Cytogenetic Profile
del(17p)/t(4;14)
Standard Risk
Median PFS, Mos
POM + LoDex (n = 77)
3.8
HiDex (n = 35)
1.1
Median PFS, Mos
POM + LoDex (n = 148)
4.2
HiDex (n = 72)
2.3
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
HR = 0.55
P < .001
HR = 0.44
P < .001
Proportion of Patients
Proportion of Patients
HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; PFS, progression-free survival; POM, pomalidomide.
PFS (Mos)
PFS (Mos)
36. Dimopoulos MA, et al. ASH Abstract 408. Reproduced with permission.

15. Induction (cycles 1-6, 28-day cycle)
Phase II Trial: Carfilzomib/Pomalidomide/ Dexamethasone in Patients With RRMM
Induction (cycles 1-6, 28-day cycle)
Carfilzomib 20 mg/m2 days 1,2 of cycle 1; 27 mg/m2 days 8,9,15,16 cycle 1, all days of following cycles
Dexamethasone
40 mg Days 1, 8, 15, 22
N = 79
Pomalidomide
4 mg Days 1-21
LMWH, low–molecular-weight heparin; QD, every day; RRMM, relapsed/refractory multiple myeloma.
Maintenance cycles: cycles 7+, 28-day cycle, carfilzomib 27 mg/m2 Days 1,2,15,16; dexamethasone and pomalidomide dosing remain unchanged
Coagulation prophylaxis with aspirin 81 mg QD or LMWH in aspirin-intolerant patients
Antiviral therapy administered with treatment
All patients refractory to previous lenalidomide treatment
42. Shah JJ, et al. ASH Abstract 690.

16. Ixazomib in Patients With RRMM Not Refractory to Bortezomib
Phase II Trial
N = 32
< MR by 2 cycles
or < PR by 4
cycles or PD
anytime
Add 40 mg/wk dexamethasone
Continue treatment until
progression
Ixazomib 5.5 mg Days 1, 8, 15
28-day cycle
2-4 cycles
≥ MR by 2 cycles
or ≥ PR by 4
cycles
Continue treatment until
progression
MR, minimal response; PD, progressive disease; PR, partial response; RRMM, relapsed/refractory multiple myeloma.
Patients receive standard supportive care, including antiemitics
Key exclusions: grade ≥ 3 neuropathy (or grade 2 with pain); previous proteasome inhibitor therapy except bortezomib
44. Kumar SK, et al. ASH Abstract 1944.

17. Impact of α-1 Acid Glycoprotein Levels on Filanesib Treatment
Single-Agent Filanesib (median 6 previous therapies)
Low*
High
All
Filanesib + Dex (median 8 previous therapies)
100 75 50 25
100 75 50 25
Survival (%)
Survival (%)
AAG, α-1 acid glycoprotein; Dex, dexamethasone; OS, overall survival.
OS (Mos)
OS (Mos)
*Low AAG is associated with longer survival.
48. Lonial S, et al. ASH Abstract 285. Reproduced with permission.

18. Akt Inhibitor Afuresertib in Combination With Bortezomib and Dexamethasone
Phase I (n = 15), dose escalation
Phase II (n = 40), safety expansion cycles 1-8, 21-day cycles
Afuresertib
Dose escalation, mg
Days 1-21
Dexamethasone
20, 40 mg
Days 1,4,8,11
IV, intravenously; PR, partial response; SQ, subcutaneously.
Bortezomib, IV or SQ
1.0, 1.3 mg/m2
Days 1,4,8,11
Phase I: modified schema; < 5 PRs, stop; ≥ 5 PRs, expand
Phase I and II: cycle 9 and beyond, afuresertib monotherapy daily
49. Voorhees PM, et al. ASH Abstract 283.

19. Summary: Treatment of Patients With Relapsed/Refractory Multiple Myeloma
Pomalidomide in combination with low-dose dexamethasone with or without carfilzomib showed activity in RR patients with a good safety profile
Ixazomib, an oral proteasome inhibitor, showed activity used alone as well as in combination with dexamethasone
Oral HDAC-6 inhibitor ACY-1215 showed clinical benefit in patients refractory to proteasome inhibitor and/or immunomodulatory agents, including bortezomib
KSP inhibitor ARRY-520 (filanesib) showed higher OS in pts with lower α-1 acid glycoprotein levels
Bortezomib-refractory patients responded to novel Akt inhibitor afuresertib combination therapy
HDAC, histone deacetylase; KSP, kinesin spindle protein; OS, overall survival; RR, relapsed/refractory.

20. Summary: Treatment of Patients With RRMM
Monoclonal antibody daratumumab well tolerated in combination with lenalidomide and dexamethasone
Antibody-drug conjugate indatuximab ravtansine with lenalidomide and low-dose dexamethasone achieved responses (including CR) at MTD
CD38 monoclonal antibody SAR showed clinical response that correlated with bone marrow plasma cell clearance
CR, complete response; MTD, maximum tolerated dose; RRMM, relapsed/refractory multiple myeloma.

21. Treatment of Multiple Myeloma: Conclusions
Lenalidomide and dexamethasone until DP is standard of care for nontransplant patients with NDMM
In NDMM transplant candidates, 3-drug regimens using immunomodulatory drugs and proteasome inhibitors pre- and posttransplant can prolong PFS and OS
Lenalidomide maintenance until DP prolongs PFS and OS, with increased risk of secondary cancers in patients who received MP or high-dose therapy and ASCT
ASCT, autologous stem-cell transplantation; DP, disease progression; MP, melphalan/prednisone; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival.

22. Treatment of Multiple Myeloma: Conclusions
Pomalidomide with low-dose dexamethasone is active in RRMM (including 17p deletion)
Carfilzomib/pomalidomide/low-dose dexamethasone increases response and is tolerated in RRMM
Novel agents, including oral proteasome inhibitors, monoclonal antibodies/immunotoxins, KSP inhibitors, Akt inhibitors, and HDAC-6 inhibitors, demonstrate promising activity in RRMM
2 vs 3 drugs in early relapse setting will be addressed in coming mos with results from ongoing phase 3 trials
Incorporation of novel therapies at all stages of disease is improving patient outcome in MM
HDAC, histone deacetylase; KSP, kinesin spindle protein; MM, multiple myeloma; RRMM, relapsed/refractory multiple myeloma.