1. Pomalidomide Plus Low-Dose Dex vs High-Dose Dex in Rel/Ref Myeloma
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San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:
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2. Introduction
Few effective treatments and no standard of care exist for patients with relapsed/refractory myeloma following failure of proteasome inhibitors (eg, bortezomib) and immunomodulatory drugs (eg, lenalidomide)
Median OS: 9 mos (3 mos without further treatment)[1]
Pomalidomide monotherapy offers limited benefit in relapsed myeloma[2,3] but is synergistic with dexamethasone (phase II studies)[4-7]
PR rates up to 35% in patients who had received bortezomib and/or lenalidomide
OS, overall survival; PR, partial response.
1. Kumar SK, et al. Leukemia. 2012;26: Schey SA, et al. J Clin Oncol. 2004;22: Streetly MJ, et al. Br J Haematol. 2008;141: Jagannath S, et al. ASH Abstract Leleu X, et al. Blood. 2013;121: Richardson PG, et al. Blood. 2013;121: Lacy MQ, et al. ASH Abstract 201.

3. Phase II MM-003 Study: Pom/LD Dex vs HD Dex in Rel/Ref Myeloma
Randomized 2:1; stratified by age (< vs > 75 yrs), disease status (refractory vs rel/ref vs bortezomib intolerant), number of prior treatments (2 vs ≥ 3)
Pom 4 mg/day on Days LD Dex 40 mg/day on Days 1,8,15,22 for 28-day cycles (n = 302)
Patients with relapsed/refractory myeloma* (N = 455)
PD or toxicity
HD Dex 40 mg/day (20 mg/day if > 75 yrs) on Days 1-4, 9-12, for 28-day cycles (n = 153)
*After ≥ 2 cycles bortezomib/ lenalidomide within previous 60 days or progressed within 6 mos of achieving PR to bortezomib
Dex, dexamethasone; DoR, duration of response; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Pom, pomalidomide; PR, partial response; QoL, quality of life, rel/ref, relapsed/refractory; TTP, time to progression.
Primary endpoint: PFS
Secondary endpoints: OS, ORR, TTP, DoR, safety, QoL
San Miguel J, et al. Lancet Oncol. 2013;14:

4. MM-003 Results: PFS (ITT Population)
Median PFS by prior treatment for Pom/LD Dex vs HD Dex
Len refractory: 3.9 vs 1.9 mos*
Len and Bort refractory: 3.7 vs mos*
Bort intolerant: 4.0 vs 2.0 mos
Len as last Tx: 4.6 vs 1.9 mos*
Bort as last Tx: 3.8 vs 1.9 mos*
Median PFS
Pom/LD Dex: 4.0 mos
HD Dex: 1.9 mos
HR: 0.48 (P < .0001)
100 80 60
Patients (%) 40
Bort, bortezomib; Dex, dexamethasone; HD, high dose; ITT, intent to treat; LD, low dose; Len, lenalidomide; PFS, progression-free survival; Pom, pomalidomide.
*P < .0001 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Mos
San Miguel J, et al. Lancet Oncol. 2013;14:

5. MM-003 Results: PFS by Subgroup
Pomalidomide + Low-Dose Dexamethasone
High-Dose Dexamethasone
HR (95% CI)
ITT population
233/302
133/153
0.48 ( )
Men
139/181
76/87
0.48 ( )
Woman
94/121
57/66
0.47 ( )
Age ≤ 75 yrs
215/278
122/141
0.50 ( )
Age > 75 yrs
18/24
11/12
0.36 ( )
Refractory
191/249
107/125
0.50 ( )
Relapsed and refractory
4/8
5/5
0.18 ( )
Intolerant to bortezomib
38/45
21/23
0.48 ( )
2 previous treatments
12/17
7/8
0.47 ( )
More than 2 previous treatments
221/285
126/145
0.48 ( )
Cytogenetics, non-high risk
72/91
41/47
0.50 ( )
Cytogenetics, moderate high risk
64/77
30/35
0.46 ( )
At least PR after cycle 2
26/51
2/3
0.58 ( )
Less than PR after cycle 2
207/251
131/150
0.58 ( )
Refractory to lenalidomide
224/286
121/141
0.50 ( )
Refractory to lenalidomide and bortezomib
176/225
95/113
0.52 ( )
Last previous treatment was lenalidomide
64/85
42/49
0.38 ( )
Last previous treatment was bortezomib
97/132
56/66
0.52 ( )
PFS, progression-free survival; PR, partial response.
0.25
0.50
1.00
2.00
Favors pomalidomide + low-dose dexamethasone
Favors high-dose dexamethasone
San Miguel J, et al. Lancet Oncol. 2013;14:

6. MM-003 Results: OS (ITT Population)
Median OS by subgroup for Pom/LD Dex vs HD Dex
Len refractory: 12.7 vs 8.0 mos
Len and Bort refractory: 11.1 vs 7.7 mos
Bort intolerant: 15.5 vs 8.6 mos
Len as last Tx: 12.3 vs 7.3 mos
Bort as last Tx: 13.1 vs 12.3 mos
Median OS
Pom/LD Dex: 12.7 mos
HD Dex: 8.1 mos
HR: 0.74 (P = .0285)
100 80 60
Patients (%) 40
Bort, bortezomib; Dex, dexamethasone; HD, high dose; ITT, intent to treat; LD, low dose; Len, lenalidomide; OS, overall survival; Pom, pomalidomide. 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
OS (Mos)
San Miguel J, et al. Lancet Oncol. 2013;14:

7. MM-003 Results: OS by Subgroup
Pomalidomide + Low-Dose Dexamethasone
High-Dose Dexamethasone
HR (95% CI)
ITT population
145/302
82/153
0.74 ( )
Men
86/181
42/87
0.84 ( )
Woman
59/121
40/66
0.61 ( )
Age ≤ 75 yrs
135/278
74/141
0.78 ( )
Age > 75 yrs
10/24
8/12
0.40 ( )
Refractory
120/249
67/125
0.76 ( )
Relapsed and refractory
3/8
2/5
0.85 ( )
Intolerant to bortezomib
22/45
13/23
0.59 ( )
2 previous treatments
7/17
5/8
0.44 ( )
More than 2 previous treatments
138/285
77/145
0.76 ( )
Cytogenetics, non-high risk
42/91
20/47
1.02 ( )
Cytogenetics, moderate high risk
47/77
21/35
0.69 ( )
At least PR after cycle 2
11/51
1/3
0.46 ( )
Less than PR after cycle 2
134/251
81/150
0.86 ( )
Refractory to lenalidomide
140/286
77/141
0.73 ( )
Refractory to lenalidomide and bortezomib
113/225
62/113
0.77 ( )
Last previous treatment was lenalidomide
41/85
29/49
0.53 ( )
Last previous treatment was bortezomib
56/132
30/66
0.87 ( )
OS, overall survival; PR, partial response.
0.25
0.50
1.00
2.00
Favors pomalidomide + low-dose dexamethasone
Favors high-dose dexamethasone
San Miguel J, et al. Lancet Oncol. 2013;14:

8. MM-003 Results: Responses
ORR significantly higher with Pom plus LD Dex vs HD Dex, both in overall population and in subgroups
DoR not significantly different regardless of previous treatment
Response
Pom + LD Dex
(n = 302)
HD Dex
(n = 153)
P Value
ORR, all patients, % 31 10
< .0001
CR or sCR 1
VGPR 5
< 1 PR 26 9
Previous treatment, %
Refractory to Len 30
Refractory to Len and Bort 28 12
.0003
Intolerant to Bort 13
.1423
Len as last treatment 33 6
Bort as last treatment 34
.0011
Median DoR, mos
7.0
6.1
.0631
Bort, bortezomib; CR, complete response; Dex, dexamethasone; HD, high dose; DoR, duration of response; LD, low dose; Len, lenalidomide; ORR, overall response rate; Pom, pomalidomide; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
San Miguel J, et al. Lancet Oncol. 2013;14:

9. MM-003 Results: Safety
AEs generally similar between arms and across subgroups
Most common grade 3/4 AEs: neutropenia, anemia, thrombocytopenia
≥ Grade 3 PN in 15% with pomalidomide plus LD Dex vs 11% with HD Dex
AE, %
Pom + LD Dex
(n = 300)
HD Dex
(n = 150)
Grade 3
Grade 4
Grade 5
Infections and infestations 24 6 4 19 5 9
Anemia 31 2 -- 32
Neutropenia 26 22 7
Fatigue
Thrombocytopenia 13 17
Pyrexia 3
< 1 1
Diarrhea
Constipation
Cough
Back pain
Dyspnea
Febrile neutropenia 8
AE, adverse event; Dex, dexamethasone; HD, high dose; LD, low dose; PN, peripheral neuropathy; Pom, pomalidomide.
San Miguel J, et al. Lancet Oncol. 2013;14:

10. Summary
In pts with relapsed/refractory myeloma, pomalidomide plus low-dose dexamethasone produced significantly longer PFS and OS than high- dose dexamethasone alone
Median PFS: 4.0 vs 1.9 mos, respectively
Median OS: 12.7 vs 8.1 mos, respectively
Benefit observed even though 50% of pts in high-dose dexamethasone arm crossed over to receive pomalidomide
ORR significantly higher with pomalidomide plus low-dose dexamethasone vs high-dose dexamethasone alone (31% vs 10%)
Treatment was well tolerated with predictable, manageable AEs
Pomalidomide plus low-dose dexamethasone is a potential new treatment option for advanced refractory/relapsed myeloma in pts who have failed bortezomib and lenalidomide
AE, adverse event; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.