7/28/2014
Winship Cancer Institute of Emory University
Current Management of Relapsed/Refractory Multiple Myeloma Kenneth C. Anderson, MD Program Director and Chief, Division of Hematologic Neoplasias Kraft Family Professor of Medicine Jerome Lipper Multiple Myeloma Center Harvard Medical School Dana‐Farber Cancer Institute
Disclosures • Consulting fees from: ─ Bristol‐Myers Squibb, Celgene, Gilead, Millennium, Onyx, and Sanofi • Stock or stock options from: ─ Acetylon Pharmaceuticals, Inc. and OncoPep
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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, induction, consolidation, and maintenance therapy Nine FDA approvals and median survival prolonged from 3-4 to 6-7 years, with additional prolongation from maintenance New approaches needed to treat and ultimately prevent relapse
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Efficacy and Toxicity by Bortezomib schedule VMP* (VISTA)
VMP twice weekly N=63
VMP once weekly N=190
CR
30%
27%
23%
PFS @ 3 years
NA
32%
35%
Any grade
44%
43%
21%
Grade 3-4
13%
14%
2%
PN discontinuation
NA
16%
4%
Total planned dose
67.6
67.6 mg/m2
46.8 mg/m2
Total delivered dose
NA
41 mg/m2
40 mg/m2
Sensory PN
*Mateos et al. J Clin Oncol 2010; PN: peripheral neuropathy
Palumbo et al ASH 2010 abstr 620
SC vs IV Bortezomib for Relapsed/Refractory Myeloma Moreau et al, ASH 2010 abstr 312
EQUIVALENT EFFICACY Peripheral Neuropathy
Bortezomib IV (N=74)
Bortezomib SC (N=148)
Pvalue*
Any PN event, %
53
38
0.04
Grade 2, %
41
24
0.01
Grade 3, %
16
6
0.03
28
23
Diabetes at baseline
11
13
Exposure to prior neurotoxic agents
85
86
Risk factors for PN, % Grade 1 PN at baseline
*P-values are based on 2-sided Fisher’s exact test
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MM-002 Ph2: POM ± LoDEX in RRMM Trial Design • Objective: To determine the efficacy and safety of POM ± LoDEX in RRMM pts • Primary endpoint: PFS • Secondary endpoints: ORR, safety, time to response, DOR, OS
a
Prior Tx with ≥ 2 cycles of LEN and BORT (separately or in combination); b Patients aged > 75 years had a starting DEX dose of 20 mg/week.
BORT: bortezomib; DOR: duration of response; LEN: lenalidomide; LoDEX: low-dose dexamethasone; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; POM: pomalidomide; pts: patients; R: randomized; RRMM: relapsed/refractory multiple myeloma; SD: stable disease; Tx: treatment. Richardson PG, et al. Blood. 2014;123:1826-1832.
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• Response rates were higher with POM + LoDEX vs. POM – In pts achieving ≥ PR, median DOR was 8.3 mos for POM + LoDEX vs. 10.7 mos for POM alone (median follow-up: 16.1 and 12.3 mos, respectively)
• 60% of pts on the POM-alone arm received LoDEX following PD
a
Data cutoff: February 1, 2013; intent-to-treat population.
CR: complete response; DOR: duration of response; EBMT: European Group for Blood and Marrow Transplantation; LoDEX: low-dose dexamethasone; MR: minimal response; PD: progressive disease; POM: pomalidomide; PR: partial response; pts: patients. Richardson PG, et al. Blood. 2014;123:1826-1832.
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MM-002 Ph2: Adverse Events • Grade 3-4 AEs were primarily hematologic POM + LoDEX (n = 112)
POMa (n = 107)
Neutropenia
41
48
Anemia
22
24
Thrombocytopenia
19
22
Leukopenia
10
7
Pneumonia
22
15
Fatigue
14
11
Dyspnea
13
8
Back pain
10
14
Hypercalcemia
1
10
Grade 3-4 Adverse Events ≥ 10% (%) Hematologic
Nonhematologic
• Other AEs of clinical interest: – Peripheral neuropathy: no grade 3-4 – DVT: 2% with POM + LoDEX; 3% with POM a
Includes patients who subsequently received LoDEX.
AE: adverse event; DVT: deep vein thrombosis; LoDEX: low-dose dexamethasone; POM: pomalidomide. Richardson PG, et al. Blood. 2014;123:1826-1832.
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.
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Pomalidomide plus Low Dose Dex is Active and Well Tolerated in Bortezomib and Lenalidomide Refractory Mutliple Myeloma
Leleu et al Blood 2013
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POM + LoDEX vs. HiDEX in RRMM MM-003 Phase 3—Trial Design
a
PD was independently adjudicated in real time. AE: adverse event; D: day; DOR: duration of response; DVT: deep-vein thrombosis; HiDEX: high-dose dexamethasone; LoDEX: low-dose dexamethasone; MM: multiple myeloma; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; POM: pomalidomide; PR: partial response; RRMM: relapsed/refractory multiple myeloma; SPM: second primary malignancy. San Miguel JF. Lancet Oncology. 2013; 14:1055-1066.
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Prior Therapies POM + LoDEX (N = 302)
HiDEX (N = 153)
5 (2-14)
5 (2-17)
Prior DEX (%)
98
99
Prior THAL (%)
57
61
Median number, n (range)
Prior ASCT (%)
71
69
Prior LEN (%)
100
100
Prior BORT (%)
100
100
Prior alkylator (%)
100
100
Refractory disease (%)
82
82
LEN refractory
95
92
BORT refractory
79
79
BORT intolerance
15
15
LEN and BORT refractory
75
74
ASCT, autologous stem cell transplant; BORT, bortezomib; DEX, dexamethasone; HiDEX, high-dose dexamethasone; LEN, lenalidomide; LoDEX, low-dose dexamethasone; POM, pomalidomide; THAL, thalidomide. San Miguel J., et al. Lancet Oncol. 2013. DOI: 10.1016/S1470-2045(13)70380-2.
Response – ITT Population • Response rate consistent among all subgroups, including LEN and BORT as last prior
a
Response based on investigator assessment and IMWG criteria, except for MR (based on EBMT criteria). bKaplan-Meier median, patients with ≥ PR only. BORT, bortezomib; CI; confidence interval; CR, complete response; DOR, duration of response; HiDEX , high-dose dexamethasone; ITT, intent to treat; LEN , lenalidomide; LoDEX, low-dose dexamethasone; MR, minimal response; ORR, overall response rate; PFS, progression-free survival; POM, pomalidomide; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response. San Miguel J., et al. Lancet Oncol. 2013. DOI: 10.1016/S1470-2045(13)70380-2.
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POM + LoDEX significantly improved PFS vs. HiDEX Subgroup
POM + LoDEXa
HiDEXa
ITT Population
253/302
138/153 0.49 (0.40-0.61)
del(17p)/t(4;14)
71/77
32/35
0.44 (0.28-0.68)
Standard-Risk Cytogenetics
126/148
63/72
0.55 (0.40-0.75)
0.25
0.5
1
Favors POM + LoDEX
HR (95% CI)
2 Favors HiDEX
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].
Forest Plot of OS Based on Prior Treatment Subgroup
HiDEXa
HR (95% CI)
176/302
101/153
0.72 (0.56-0.92)
≤ 3 Prior Tx
41/70
22/33
0.56 (0.33-0.96)
> 3 Prior Tx
135/232
79/120
0.76 (0.58-1.00)
ITT Population
Prior THAL
102/173
64/93
0.75 (0.55-1.03)
No Prior THAL
74/129
37/60
0.66 (0.45-0.99)
LEN Ref
168/286
94/141
0.70 (0.55-0.90)
BORT Ref
142/238
79/121
0.77 (0.58-1.01)
LEN and BORT Ref
135/225
74/113
0.77 (0.58-1.02)
LEN as Last Prior
47/85
32/49
0.56 (0.36-0.88)
BORT as Last Prior
76/134
39/66
0.92 (0.63-1.36)
0.25
0.5
Favoring POM-LoDex a
POM + LoDEXa
1
2 Favoring HiDEX
Number of events/number of pts.
San Miguel JF, et al. ASH 2013 [abstract 686].
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Safety Profile – Grade 3/4 AEs in ≥ 20% POM + LoDEX (n = 300) Grade 3/4 hematologic AEs (%)
Total
Grade 3
HiDEX (n = 150) Grade 4
Total
Grade 3
Grade 4
Anemia
52
31
2
51
32
5
Neutropenia
51
26
22
21
9
7
Thrombocytopenia
30
9
13
29
9
17
Infections
68
24
6
53
19
5
Fatigue
34
5
–
27
6
–
Pyrexia
27
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