Optimizing treatment for relapsed
myeloma
July 2004 Myeloma “101”
M.L.Gray
Current Treatment Goals

Cures are possible but should not be the
overarching goal



30% of CR’s can last 10% or more
Aim for long term complete remission
Preserve quality of life




Reduce fatigue
Control pain
Protect from infections
Improve ADLs / Performance Status
July 2004 Myeloma “101”
M.L.Gray
Multiple Myeloma Treatment Lines in TransplantEligible Patients
Current Paradigm
Frontline treatment
Maintenance
Relapsed
Maintenance
Rescue
Risk Stratification?
Induction
Alkylators
Steroids
Thalidomide
Lenalidomide
Bortezomib
Anthacyclines
e
Consolidation
SCT
Thalidomide
Steroids
Bortezomib
Lenalidomide
Alkylators
Steroids
Thalidomide
Bortezomib
Anthacyclines
Carfilzomib
Pomolidomide
Bendamustine
National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology
Multiple Myeloma (Version 1.2011). http://www.nccn.org/. Accessed October 13, 2010.
Patient Case
 65-year-old male presents with anemia
• Initial workup: hemoglobin = 9.5, normal CBC and platelets
 Patient is referred to a local hematologist, an
extensive workup finds
• IgG kappa protein (3.5 g/dL) with reciprocal depression of
the other immunoglobulins, negative UPEP
• 40% plasma cells in the bone marrow with normal
cytogenetics by standard chromosomal analysis and del13
by FISH
• Diffuse lytic disease
• b2-microglobulin = 3.9, albumin = 3.7
UPEP, urine protein electrophoresis.
Patient Case Continued
• He begins induction therapy with thalidomide / bortezomib
/ dex (VTD)
• After 2 cycles he develops paresthesia not interfering with
his function
• After 4 cycles he achieves a PR (75% reduction)
• Stem cells are collected and he receives a single ASCT
• He achieves a CR post-ASCT and declines maintenance
therapy at day 100
• He continues to experience grade 1 peripheral
neuropathy
 15 months after his stem cell transplant, he has a
clinical relapse including new lytic lesions
ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR,
complete response.
Natural History of Relapse
Types of Relapse
Alegre A et al. Haematologica 2002;87(6):609-614.
Multiple Myeloma
Expectations for Survival After Relapse
Survival as a Function of Era-SCT Patients
8
Which of the following should NOT be considered
when developing a re-treatment plan?
• Age
• Prior Therapy
• Type of relapse
• Duration of remission
• Comorbidities
Factors in Selecting Salvage Therapy
DISEASE-RELATED
DOR to initial therapy
FISH / cytogenetics
REGIMEN-RELATED
PATIENT-RELATED
Prior drug exposure
Pre-existing toxicity
Toxicity of regimen
Co-morbidities
Mode of administration
Age
Previous SCT
Performance status
Stage generally does not influence salvage therapy choice.
Lonial S. ASH Education Book. 2010;303-309.
DOR, duration of response; FISH, fluorescent in situ
hybridization; SCT, stem cell transplant.
Relapse Approaches
CONSIDER CLINICAL TRIAL WITH A NOVEL AGENT
EARLY
LENALIDOMIDE-BASED
Initial therapy with bz
Underlying PN
BORTEZOMIB-BASED
Initial therapy len / thal
Long DOR with prior bz
Renal dysfunction
TRANSPLANT
No previous SCT
Long remission post-SCT
AGGRESSIVE, RAPID, OR MULTIPLE RELAPSE
CT-BASED
SCT-BASED
DCEP vs DT-PACE
Oral vs IV CT
PS plays an important role
Likely to be short-lived
Quick disease control
Reconstitute marrow
CT + NOVEL AGENT
?
Combinations of len
and / or bz with other
agents
Consider combination therapy. Don’t wait for symptomatic relapse.
Lonial S, et al. Clin Cancer Res. 2011;17:1264-1277.
Bz, bortezomib; PN, peripheral neuropathy; len,
lenalidomide; thal, thalidomide; CT, chemotherapy;
SCT, stem cell transplant; PS, performance status.
Patient Case Continued
 15 months after his stem cell transplant, he has a
clinical relapse including new lytic lesions
 Treat or not
• Yes, symptomatic relapse
 Single or Combo
• Lets look at the data
 Retransplant?
• Lets look at the data
ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR,
complete response.
Clinical Considerations for
Relapsed/Refractory Disease
• Disease characteristics/prior therapy
–
–
–
–
Aggressiveness of relapse
Relapsed or relapsed and refractory disease
“High risk disease”
Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)
• Toxicity considerations
–
–
–
–
Peripheral neuropathy
Thrombotic risk
Myelosuppression
Impact of prior therapies (eg, SCT, other cumulative toxicity)
How do we treat a patient in first relapse?
Sequencing of therapy is important
Issues
Treat or Not to Treat
Single Agent vs Combinations
Classes of Drugs With Anti-MM Activity
Steroids
Immunomodulatory
Agents
Proteasome
Inhibitors
Cytotoxic
CT
HDAC
inhibitors
mTOR
inhibitors
mAbs
Prednisone
Thalidomide
Bortezomib
Melphalan
Vorinostat
Perifosine
Elotuzumab
Dexamethasone
Lenalidomide
Carfilzomib
Cyclophosphamide
Panobinostat
Pomalidomide
MLN9708
PLD
ONX 0912
DCEP
Marizomib
BCNU
CEP-18770
Bendamustine
Novel Agents as Monotherapy
Without Steroids
Regimen
Bortezomib
(APEX)
Thalidomide
Lenalidomide
Phase
3
n
331
CR + PR CR + nCR
43%
16%
Richardson, et al.
Blood. 2005;106
(abstract 2547)
712
28.2%
1.6%
Prince, et al.
Leuk Lymphoma.
2007;48:46
1629
29.4%
1.6%
Glasmacher, et al.
Br J Haematol. 2006;132:584
102
17%
4%
Richardson, et al.
Blood. 2006;108:3458
2
2
Reference
Proteasome inhibitor bortezomib has the best single agent activity
Thal + Dex vs. Combination Chemotherapy
First Relapse
Thalidomide + Dexamethasone
Combination Chemotherapy
N
62
82
PFS
17 months
11 months
OS at 3 years
60%
26%
OS at 3 years 60% vs.26%
PFS median 17 vs.11 months
THAL 100 mg/day and DEX 40 mg (days 1–4 of each month)
CC: MP, VAD, intermed dose Cytoxan, VMCP-VBAP
Second Relapse
Thalidomide + Dexamethasone
Combination Chemotherapy
Palumbo A, et al. Hematol J. 2004;5:318-324.
N
58
38
PFS
11 months
9 months
OS at 3 years
19
19
Pooled Analysis of MM-009 and MM-010 Data: Response,
TTP and OS According to Number of Prior Therapies
1 Prior Therapy
≥ 2 Prior Therapies
Response Rate (%)
80
65%*
PR + CR
PR (>50%)
58%*
60
CR (IF-)
40
*EBMT Criteria
26%
20%
20
0
Len/Dex
n=124
14.5*
Dex
n=124
4.7
Len/Dex
n=229
Dex
n=227
9.6
4.7
Median TTP (months)
33.3
27.3
Median OS (months)
P<0.05
39.1
33.6
Weber DM, et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA.
Pooled Analysis of MM-009 and
MM-010 Data: Updated OS
Survival Benefit Retained Despite 47% Crossover
100
Patients (%)
80
Len/Dex
Median, 35 months
(58% remain alive)
60
40
P=0.015*
Plac/Dex
Median, 31 months
20
0
0
10
20
30
40
Overall Survival (Months)
*P value from log-rank test (patients analyzed for extended follow-up remained in original groups
despite crossover)
Weber D, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:412.
50
Impact of Prior Thalidomide Therapy:
Pooled Analysis of MM-009 and MM-010 Data
Thal Naïve vs. Thal Exposed
Median Time from Diagnosis: 2.8 years vs. 4.0 years (P<.05)
Median Lines of Prior Therapy: 2 vs. 3 (P<.05)
n
Thal Naïve
Prior Thal
Progressed (CR/PR)
SD
Refractory (PD)
226
127
54
31
20
ORR (≥PR),
%
65
54
43
45
50
Median TTP,
months
13.8
8.3
7.0
7.0
7.1
Weber DM, et al. Presented at 49th ASH Annual Meeting; December 8-11, 2007; Atlanta, GA.; Weber DM, et
al. N Engl J Med. 2007;357:2133-2142.; Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132.
APEX: Bortezomib
Early vs. Late Relapse
1 prior therapy
n = 132
> 1 prior therapy
n = 200
7.0
4.9
CR (%)
10%*
7%†
CR + PR (%)
51%*
37%†
8.1
7.8
89%
73%
Bortezomib
Median TTP (months)
Median Duration
of Response (months)
1-year Survival
* Evaluable patients, response to bortezomib after 1 prior therapy: n = 128
† Evaluable patients, response to bortezomib after >1 prior therapy: n = 187
Sonneveld P, et al. Haematologica. 2005;90:146-147. Abstract P140.721.; Data on file; Millennium
Pharmaceuticals, Inc.
Updated APEX Results
OS
Proportion of Patients
1.0
0.8
Bortezomib
0.6
0.4
Dexamethasone
29.8 months
P=.0272
23.7 months
0.2
0.0
0
90
180 270 360 450 540 630 720 810 900 990 1080 1170
Time (Days)
• Superior survival despite >62% of HD dexamethasone patients
crossing over to bortezomib
– 1-year survival rate: 80% vs. 67%; P=.0002
Richardson PG, et al. Blood. 2007;110:3557-3560.
Bortezomib Combination
Therapies in Relapse
Overall
Median
CR/nCR
Median
Response
PFS
Rate (%)
OS (mos)
Rate (%)
(mos)
Author/Year
N
Regimen
Pineda-Romané/2008
85
BTD
63
22
–
22
Jakubowiak/2005
20
BD + PLD
56
33
–
–
Biehn/2007
22
B + PLD
63
36
9.3 (TTP)
38.3
Popat/2005
22
B + Iv Mel +/- D
43
5
6.8 (TTP)
–
Palumbo/2007
30
V Mel PT
67
17
61% (1 yr)
84% (1 yr)
Reece/2008
37
B + Cy + P
95
54
>12
>12
B = bortezomib; T = thalidomide; D = dexamethasone; PLD = pegylated liposomal doxorubicin;
Mel = melphalan; P = prednisone; Cy = cyclophosphamide; PFS = progression-free survival; nCR = near
complete response.
Kaufman J et al. Curr Hematol Malig Rep. 2009;4:99-107.
23
Lenalidomide Combination
Therapies in Relapse
Author/Year
N
Regimen
Overall
Response
Rate (%)
Schey/2009
31
LCD
81
36 (VGPR)
–
–
Knop/2009
66
LDoD
73
15
40 weeks
88% (1 year)
Reece/2009
15
LCP
74
45 (VGPR)
–
–
Baz/2006
52
L PLD ViD
75
29 (nCR)
1 year
84% (1 year)
Richardson/2009
35
LBV+/- D
60 >MR
8
7.7 months
37 months
Anderson/2009
62
LBVD
69
26
12 months
29 months
CR/nCR
Rate (%)
Median
PFS
Median
OS
L = lenalidomide; C = cyclophosphamide; D = dexamethasone; DO = doxorubicin; P = prednisone;
PLD = pegylated liposomal doxorubicin; Vi = vincristine; B = bortezomib.
Schey S et al. ASH 2008 Annual Meeting. Abstract 3707; Knop S et al. Blood. 2009;113:4137-4143;
Reece DE et al. ASH 2009 Annual Meeting. Abstract 1874; Baz R et al. Ann Oncol. 2006;17:1766-1771;
Richardson PG et al. J Clin Oncol. 2009;27:5713-5719; Anderson KC et al. 2009 ASCO Annual Meeting.
Abstract 8536.
24
Main Randomized Trials of Treatment
of Relapsed/Refractory MM
ORR
(%)
CR
(%)
TTP
(mos)
OS
(%)
Bortezomib
vs. dexamethasone
43 vs. 18
9 vs. 1
6.2 vs. 3.5
80 vs. 66 (1-yr)
Bortezomib + PLD
vs. bortezomib
44 vs. 41
4 vs. 2
9.3 vs. 6.5
76 vs. 65
(15 mos)
Lenalidomide/dexame
thasone
vs. dexamethasone
61 vs. 19.9
14.1 vs. 0.6
11.1 vs. 4.7
29.6 vs. 20.2 mos
Lenalidomide/dexame
thasone
vs. dexamethasone
60.2 vs. 24
15.9 vs. 3.4
11.3 vs. 4.7
NR vs. 20.6 mos
Combinations
ORR = overall response rate; CR = complete response; TTP = time to progression; NR = no response.
Richardson et al, 2007; Orlowski et al, 2007; Weber et al, 2007; Dimopoulos et al, 2007.
Additional Bortezomib and
Lenalidomide Combinations
Study
Regimen
N
Responses
Frequent G3/4 AEs
TCP, leukopenia,
infection, PN, HZV,
fatigue, anemia,
hypotension
Kropff, et al1
VCD
50
16% CR
66% PR
Morgan, et al2
CVD
47
31% CR
75% ORR
TCP, neutropenia, PN,
infection
Reece, et al3
VCP
37
>50% CR
95% ORR
Nausea, TCP,
neutropenia
Len + PLD
62
29% CR/nCR
75% ORR
Baz4
1Kropff
Myelosuppression
M, et al. Br J Haematol. 2007;138:330-337. Comment in: Br J Haematol. 2008;140:115-116.
FE, et al. Haematologica. 2007;92:1149-1150. 3Reece DE, et al. J Clin Oncol. 2008;26:47774
4783. Baz R, et al. Ann Oncol. 2006;12:1766-1771.
2Davies
PUTTING IT ALL TOGETHER
Indolent, Slow, First Relapse
Likely Single-Agent Therapy With Bz or Len/Thal
IMiD-Based Salvage
Lenalidomide
Thalidomide
Bortezomib-Based
Salvage
• Initial Tx with Bz
• Initial Tx with IMiD
• May consider single
agent w/o Dex
• Previous Bz therapy
but good or long
response
• Underlying PN
Transplant-Based
Salvage
• Transplant not part
of initial therapy
• Long remission
post transplant
• Renal dysfunction
PN = peripheral neuropathy.
Lonial S et al. Clin Cancer Res. 2011;17:1264-1277. Permission requested.
28
Aggressive, Rapid,
Multiple Relapse
Likely Combination Therapy
Do Not Wait for Symptomatic Relapse
Chemotherapy-Based
Salvage
Chemotherapy + Novel
Agent
• DCEP vs DT-PACE
• Combinations of Len/Bz
and other chemo agents
• Oral vs IV chemo
Transplant-Based
Salvage
• Likely to be short lived
• Quick disease control
• Reconstitute marrow
• PS of patient plays
important role
PS = performance status.
Lonial S et al. Clin Cancer Res. 2011;17:1264-1277. Permission requested.
29
Comparison of the triple (bortezomib-thalidomide-dexamethasone) and dual (thalidomidedexamethasone) treatment groups.
Garderet L et al. JCO 2012;30:2475-2482
©2012 by American Society of Clinical Oncology
Patient Case Continued
• 15 months after his stem cell transplant, he has a
clinical relapse including new lytic lesions
• Treat or not
– Yes, symptomatic relapse
• Single or Combo
– I would use combination
•
•
•
•
VTD
VRD
Carfilzomib based
DTPace if LDH elevated
• Retransplant
– Difficult question if transplant naïve definitively yes.
ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR,
complete response.
Patient Case Continued
• Receives VTD x 12 months and is placed on low
dose thalidomide maintenance. Within 2 months
has new lytic lesions and increasing paraprotein
peak.
• Treat or not?
• Single or Combo?
• Retransplant?
ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR,
complete response.
Response Duration Decreases With
Successive Therapies
• 578 patients; median age 65 years (follow up 55 months)
• Overall survival
– One year 72%
– Two years 55%
– Three years 22%
• 84% died within five years
Figure 3. Duration of response to each treatment
Median response
duration (months)
12
10
8
6
4
2
0
1
2
3
4
Treatment number
Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874.
5
6
Time to Progression After SCT Correlates
With OS After Initial Relapse
Median estimated survival from relapse (months)
35
30
25
20
15
10
5
0
6
12
18
24
30
Time to relapse from SCT (months)
Kumar SK, et al. Bone Marrow Transplant. 2008;42:413-420.
36
Overall survival from time of relapse after
ASCT- Impact of New Agents as Salvage
Therapy
30.9 months (95% CI; 23.6, 38.2
14.8 months (95% CI; 11.3, 18.4
Kumar SK, et al. Blood. 2008;111:2516-2520.
Recurrent Myeloma
• 45-year-old woman
• κ light chain multiple myeloma diagnosed
January 2001
– Durie-Salmon Stage IIIA, ISS Stage 2
• Laboratory findings
–
–
–
–
–
Total proteinuria 5.82 g/day
Bence Jones protein (BJP) 3.6 g/day
Hypogammaglobulinemia
Albumin 3.9 g/dL
β2-microglobulin 4.7 mg/L
Recurrent Myeloma
• Bone marrow biopsy
– Cellularity 80% with 25% plasma cells
– Cytogenetics 46, XX, inversion 9 (p11;q13)
• FISH not done
• Skeletal survey: extensive lytic bone disease with
healing fractures of left 7th and the 8th ribs
• MRI of the spine: diffuse hyperintense homogenous
signal on STIR sequence
• MRI of the pelvis: diffuse marrow infiltrative changes
due to myeloma
Recurrent Myeloma
• Treatment
– Vincristine 0.4 mg, doxorubicin 9 mg/m2
Days 1-4; dexamethasone 40 mg Days 1-4, 9-12,
17-20; x 4 cycles
– Followed by high-dose melphalan and stem cell
transplant on July 11, 2001
• Achieved complete remission
• Maintained on pamidronate and prednisone
x 1 year
First Relapse Five Years Later
• First relapse January 11, 2006
–
–
–
–
–
–
–
–
Urine total protein 550 mg/day
Creatinine clearance 84 mL/minute
BJP 100 mg/day
Urine IFE free κ light chain
Serum free κ 750 mg/L
Free λ 15 mg/L
κ:λ ratio 50
Multiple new lytic lesions of the skull
• MRI spine and pelvis January 11, 2006
– New focal lesion at L3 vertebral body
Second Relapse After Failure of IMiDs
•
•
Treated with thalidomide and weekly
dexamethasone for 6 months → stable disease
Switched to lenalidomide and weekly
dexamethasone x 3 months → stable disease
Third Relapse 18 Months Later
•
•
•
•
•
•
•
Treated with bortezomib and dexamethasone x 4 cycles
Achieved CR
Painful peripheral neuropathy grade 2
Discontinued treatment December 2006
PET/CT June 2008
– 1 cm focal hypermetabolic area in the inferior aspect of the left scapula
– 2.2 cm focal hypermetabolic area in the region of right posterior superior
iliac spine, with associated lytic changes
Laboratory findings
– Free κ 117 mg/L
– Free λ 15.6 mg/L
– κ:λ ratio 7.5
– Urine total protein 182 mg/day
– BJP 60 mg/day
– Urine immunofixation electrophoresis: free κ
Treated with VRD with progressive disease
CTC=common toxicity criteria
Definition of Relapsed/Refractory MM

Relapsed
– Relapse off therapy

Relapsed/Refractory
– Relapse while on, or within 60 days of
discontinuing, therapy
– Unmet medical need
• Lack of drug approval for relapse/refractory to IMiD,
bortezomib, alkylators, anthracyclines, and steroids
IMiD = immunomodulatory drugs.
Anderson et al, 2008.
Once Treatment Fails,
Trouble Begins
Overall Survival From Start of Therapy
by Regimen Number
Survival with Bz/Len Refractory Ds
100
Survival (%)
0.4
20
0
2
4
6
8
Years From Start of Regimen
Kumar S. Mayo Clin Proc. 2004;79:867-874.
10
173/231
9 (7, 11)
Event-Free Survival
222/291
5 (4, 6)
60
40
0
Overall Survival
80
0.2
0.6
0.8
Regimen 1
Regimen 2
Regimen 3
Regimen 4
Regimen 5
Regimen 6
0
Cumulative Probability (%)
1.0
Median
Events/N (Months)
0
12
24
36
48
60
Months From Time Zero
Kumar SK et al. Leukemia. 2012;26:149-157.
43
NEWER AGENTS
44
Comparison of
Proteasome Inhibitors
Bortezomib (reversible)
Carfilzomib (irreversible)
CEP 18770 (reversible)
NPI
Bortezomib
b1
MLN9708 (reversible)
NPI-0052 (irreversible)
Postglutamyl
Tryptic
NPI
b1
Postglutamyl
b7
b3
b7
b6
b4
b6
Tryptic
b2
b3
NPI
Chymotryptic
Chymotryptic
b5
b5
b4
45
Study 004: Phase 2 Trial of
Single-Agent Carfilzomib in
Relapsed/Refractory Multiple Myeloma
Carfilzomib IV
qd x 2 for 3 weeks (28-day cycle for up to 12 cycles)
Study population (N = 165)
• Measurable disease
Cohort 1
20 mg/m2
• Responsive to 1 prior therapy
• Relapsed and/or refractory MM
following 1-3 prior treatment
regimens
• ECOG PS 0-2
•
•
Cohort 2†
20 mg/m2 cycle 1
Escalation to 27 mg/m2
in all subsequent cycles
BOR-treated*
(n = 35)
BOR-naive
(n = 59)
BOR-naive
(n = 70)
Primary endpoint: ORR (CR + IVGPR + PR [IMWG criteria])
Secondary endpoints: CBR (ORR + MR [EBMT criteria]), DOR, PFS, TTP, OS, safety
–
OS, TTP, response rate (EBMT criteria), safety
*Results for bortezomib (BOR)-treated cohort have been reported previously (Vij R et al.
J Clin Oncol. 2010. Abstract 8000).
†Subjects who enrolled under amended protocol allowing dose increase to 27 mg/m2 or who
re-consented before Cycle 4 start were grouped in Cohort 2.
Vij R et al. ASH 2011 Annual Meeting. Abstract 813.
46
Results of the PX-171-004 Phase II Trial –
Carfilzomib in Relapsed and/or Refractory MM
Bortezomib-naïve
Bortezomib-treated
patients (Wang, et al)
patients (Siegel, et al)
N = 59
N = 35
Evaluable patients
54
33
Complete response
1 (2%)
1 (3%)
Very good partial response
5 (9%)
1 (3%)
35%/15%/22%
12%/12%/39%
8.4 months
10.6 months
Grade 1/2: 12%
Grade 1/2: n = 3 (9%)
Grade 3: 2%
Grade 3: n = 1 (3%)
PR/MR/SD
Duration of response (≥
PR)
Treatment-emergent
peripheral neuropathy
Wang L, et al. Blood (ASH Annual Meeting Abstracts). 2009;114:302.
Siegel D, et al. Blood (ASH Annual Meeting Abstracts). 2009;114:303.
Single-Agent Anti-Tumor Activity:
Bortezomib-Naive Response-Evaluable
Population by Cohorts
Cohort 1
20 mg/m2
(n = 59)
Cohort 2
20/27 mg/m2
(n = 67)*
Duration of response
n = 25
n = 35
Median, (95% CI)
13.1 (7.2-NE)
NR (NE-NE)
n = 35
n = 43
Median, (95% CI)
11.5 (6.2-NE)
NR (NE-NE)
Time to progression
n = 59
n = 67
Median, (95% CI)
8.3 (6.0-12.3)
NR (11.3-NE)
n = 25
n = 35
1.0 (0.5, 3.7)
1.9 (0.5, 3.7)
n = 35
n = 43
0.5 (0.5, 6.5)
0.5 (0.5, 5.9)
Median, months
Duration of clinical benefit response
Time to response
Median, (min, max)
Time to clinical benefit response
Median, (min, max)
*3 patients were not evaluable for response as they did not have either baseline or post-baseline assessment.
NE = not estimable; NR = not reached.
Vij R et al. ASH 2011 Annual Meeting. Abstract 813.
48
Progression-Free Survival:
Response Evaluable Population
Vij R et al. ASH 2011 Annual Meeting. Abstract 813.
49
Overall Survival:
Response Evaluable Population
Vij R et al. ASH 2011 Annual Meeting. Abstract 813.
50
Pomalidomide Summary
Study
Richardson et
Lacy et
N
Regimen
Median Prior
Therapies
ORR
(%)
MR
(%)
38
Pom (2-5 mg daily for
21/28 days)  dex
6
25
50
120
Pom (4 mg daily for
21/28 days)  dex
5
25
38
35
Pom (2 mg daily) +
low-dose dex
6
26
49
35
Pom (4 mg daily) +
low-dose dex
6
28
43
43
Pom (4 mg 21/28
days) + low-dose dex
4
18
NR
41
Pom (4 mg 21/28
days) + low-dose dex
4
16
NR
al1
al2
Leleu et al3
Pom = pomalidomide; dex = low-dose dexamethasone; ORR = overall response rate;
MR = marginal response.
1. Richardson P et al. ASH 2010 Annual Meeting. Abstract 864.
2. Lacy MQ et al. Blood. 2011;118;2970-2975.
3. Leleu X et al. ASH 2010 Annual Meeting. Abstract 859.
51
Pomalidomide: Previous Phase 2
Studies in RRMM
Prior
Lines*
ORR
(≥ PR)
(%)
Phase
N
Pom.
schedule
Richardson et al1
2
221
21/28
Pom: 4 mg vs
Pom 4 mg + Dex
Len & Bort
refractory
5
13 vs 34
Lacy et al2
2
34
28/28#
Pom: 2 mg
Dex: 40 mg/week
Len refractory
4
32
Lacy et al3
2
70
28/28*
Pom: 2 and 4 mg
Dex: 40 mg/week
Len & Bort
refractory
6
25 and 29
Study
Treatment
Population
Len = lenalidomide; bort = bortezomib; Pom = pomalidomide; RRMM = relapsed/refractory
multiple myeloma.
*Median prior therapies; †continuous.
1. Richardson P et al. ASH 2011 Annual Meeting. Abstract 634.
2. Lacy MQ et al. Leukemia. 2010;24:1934-1939.
3. Lacy MQ et al. Blood. 2011;118:2970-2975.
52
Pomalidomide: IFM 2009-2012
Study Design
Arm A – Cycle 21 days
• Pomalidomide 4 mg oral/d, Days 1–21
Dexamethasone 40 mg oral/Weeks 1, 8, 15, 22
• Aspirin/LMWH continue
Key inclusion criteria:
• Relapsed MM
• Resistant or refractory to both
lenalidomide and bortezomib
• Measurable disease (central lab)
• ANC >1 x109/L; Platelets ≥ 75 x109/L;
Hb ≥ 8 g/dL
Arm B – Cycle 28 days
• Pomalidomide 4 mg oral/d, Days 1–28
Dexamethasone 40 mg oral/Weeks 1, 8, 15, 22
• Aspirin/LMWH continue
6 patients per arm
DMC – TOLERANCE
Rule: no difference
N = 84 randomized
Primary objective:
Response rate (PR and
better)
according
to
IMWG in either arm
17 patients per arm
DMC – EFFICACY
Rule: 4 ≥ PR /arm
• Creatinine clearance ≥50 mL/min
40 patients per arm
Until progression
(relapse or refractory)
LMWH = low molecular weight heparin; IMWG = International Myeloma Working Group.
Leleu X et al. ASH 2011 Annual Meeting. Abstract 812.
53
Time to Events
0.2
B
No. at Risk 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
1.0
0.8
0.6
B
0.4
A
A
0.2
0.4
0.6
0.8
HR = 1.18 [0.65]
Log-rank P = 0.5875
KM median: A = 9.23 [5.42]
KM median: B = 7.36 [4.60, 9.96]
Events: A = 21, B = 23
HR = 0.90 [0.46, 1.73]
Log-rank P = 0.7453
KM median: A = 13.44 [8.90, 13.93]
KM median: B = 15.26 [9.17]
Events: A = 19, B = 18
0
Survival Distribution Function Estimate
1.0
Overall Survival
Median 13.4 months
(95%CI, 9.8-)
0
Survival Distribution Function Estimate
Time to Progression
Median 9.1 months
(95%CI, 5.8-10.0)
No. at Risk 0
1
2
3
4
5
6
7
8
9
10
11
12
A
43 36 32 30 23 22 20 19 17 15 11
8
6
2
0
0
A
43
42
40
38
36
32
31
30
29
26
21
14
9
B
41 37 32 27 23 21 20 18 16 14
6
2
2
0
0
B
41
40
39
34
32
32
30
29
27
26
19
15
8
7
Time From First Intake (months)
Leleu X et al. ASH 2011 Annual Meeting. Abstract 812.
Time From First Intake (months)
54
Response by Prior Therapy:
ITT, IRC
21/28
N = 43
28/28
N = 41
Total
35
34
34.5
Lenalidomide
36
36
36
Bortezomib
32
26.5
29
Both lenalidomide and bortezomib
34
28
31
Last prior therapy
33
31
32
25
31
30
≥ PR
All patients %
Refractory to* %
Del17p and/or t(4;14)
*Refractory to as per IMWG criteria.
Leleu X et al. ASH 2011 Annual Meeting. Abstract 812.
55
Adverse Events
21/28
N = 43
28/28
N = 41
Total
Serious AEs
33
41.5
37
Any grade 3 and 4 AEs
91
83
87
72
71
71
Anemia
33
32
32
Neutropenia
63
56
59.5
Thrombocytopenia
28
24
26
23
27
25
14
5
9.5
AEs, %
Blood and lymphatic system disorders
General disorders and administration site conditions
Asthenia
Discontinued due to drug-related AE, n = 2.
Leleu X et al. ASH 2011 Annual Meeting. Abstract 812.
56
Blockade of Ubiquitinated
Protein Catabolism
Protein
Ub Ub
Protein aggregates
(toxic)
Ub
Ub
Ub
26S Proteasome
Ub
HDAC6
Tubacin
LBH, vorinostat
Ub Ub
Bortezomib
HDAC6
Dynein
Ub
Ub
HDAC6
Dynein
Microtubule
Aggresome
Ub Ub
Lysosome
Ub Ub
Ub
Ub
Autophagy
Tai YT et al. Cancer Res. 2005;65:5898-5906; Hideshima T et al. Clin Cancer Res. 2005;11:8530-8533.
Permission requested; Catley L et al. Blood. 2006;108:3441-3449.
57
VANTAGE PN088:
Phase 3 Trial Design
Patients enrolled
Dosing schedule
Analysis populations
Bortezomib
Intent-to-treat (ITT)
PFS, TTP, OS
(N = 637)
• Progressive disease after
the most recent treatment
• 1 to 3 prior treatment
regimens
• Bortezomib-sensitive
patients
•
in combination with
Vorinostat 400 mg OR placebo
Once daily on Days 1-14
(21-day treatment cycle)
Primary endpoint
–
•
1.3 mg/m2 IV on Days 1, 4, 8, 11
Bortezomib + Vorinostat
(N = 317)
Bortezomib + Placebo (N = 320)
Full analysis set (FAS)*
ORR, safety
Bortezomib + Vorinostat
(N = 315)
Bortezomib + Placebo (N = 320)
PFS†
Secondary endpoints
–
OS, TTP, response rate† (EBMT criteria), safety
*Constitutes
†Assessed
patients who received treatment after randomization.
by an Independent Adjudication Committee.
EBMT = European Group for Blood and Marrow Transplantation.
Dimopoulos MA et al. ASH 2011 Annual Meeting. Abstract 811.
58
EBMT Response Assessment (IAC):
Response-Evaluable Population
CBR = 71% vs 54%, P<0.0001
ORR = 56% vs 41%, P<0.0001
Bortezomib + vorinostat (N = 315)
Bortezomib + placebo (N = 320)
IAC = Independent Adjudication Committee; SD = stable disease.
Dimopoulos MA et al. ASH 2011 Annual Meeting. Abstract 811.
59
PFS (%)
Progression-Free Survival (IAC)
100
90
80
70
60
50
40
30
20
10
0
BTZ + Vorinostat
BTZ + Placebo
Events
201/317
216/320
Median PFS (95% CI)
7.63 months (6.9-8.4)
6.83 months (5.7-7.7)
HR (95% CI)
P value
0.774 (0.64-0.94)
0.01
BTZ + Vorinostat
BTZ + Placebo
0
5
No. at Risk:
BTZ + Vorinostat 317
BTZ + Placebo
320
196
157
10
15
Time (months)
75
58
14
12
20
25
3
4
0
0
Dimopoulos MA et al. ASH 2011 Annual Meeting. Abstract 811.
60
OS (%)
Overall Survival
100
90
80
70
60
50
40
30
20
10
0
BTZ + Vorinostat
BTZ + Placebo
Events
71/317
80/320
Median OS (95% CI)
HR (95% CI)
NA
0.86 (0.62 – 01.18)
28.1 months (28.1 – NA)
P value
0.35
BTZ + Vorinostat
BTZ + Placebo
0
5
10
No. at Risk:
BTZ + Vorinostat 317
BTZ + Placebo
320
291
286
238
235
15
20
Time (months)
120
124
43
48
25
30
12
16
1
0
NA = not available.
Dimopoulos MA et al. ASH 2011 Annual Meeting. Abstract 811.
61
Second Salvage ASCT for Relapsed Myeloma
Princess Margaret Hospital (N=79)
• Median 60 years (39-72)
• Median TTP after 1st transplant 2.72 years (0.81-8.26)
• Median interval between transplants 3.61 years (1.63-9.59)
• NRM 2.5%
• Response after 2nd transplant: 15% CR/nCR, 78% PR, 8%
MR/SD
• Results after 2nd transplant based on TTP after 1st transplant
Group
N
Median PFS (mos)
Median OS (mos)
All
79
18.5
52.8
<24 mos
15
12.7
42.2
24-36 mos
30
17.0
52.7
>36 mos
34
32.6
NYR
Mikhael J, et al. Blood 2009; 114: abstract #1217
Second Salvage AlloSCT for
Myeloma
Study
N
Median FU
(mo)
Response
rate (CR) (%)
Gerull/20051
52
19
--
~6
~16
Quazilbash/20062
26
30
69 (31)
7.3
13
Majolino/20073
41
--
--
~28
~30
van Dorp/20074
23
--
--(4)
12
--
de Lavallade/20085
18
36
61
~24
~36
Kroger/20096
96
43
95 (46)
10.6
22.6
1Gerull
Median
Median
PFS (mos) OS (mos)
S, et al. Bone Marrow Transplant 2005; 36: 963-939; 2Quazilbash MH, et al. Cancer 2006; 106; 1084-1089;
3MajolinoI et
al. Leuk Lymphoma 2007; 48: 759-766; 4van Dorp S, et al. Neth J Med 2007; 65: 178-184; 5 de Lavallade
H, et al. Bone Marrow Transplant 2008; 41: 953-960; 6Kroger N, et al. Br J Haematol 2010; 148: 323-331.
CIBMTR Data
Antibodies
•
•
•
•
BT-062 (CD138 + maytansinoids)
CD40
CD200
CD56
Bortezomib combinations have activity:
Bz + CNTO 328 (anti IL6 ab)1: ORR of 57% with TTP of
8.7 months (1-3 prior lines)
Bz + Elotuzumab (anti CS1 ab)2: ORR of 48% TTP of 9.4 months
(median of 2 prior lines)
1. Rossi JF et al. ASH 2008 Annual Meeting. Abstract 1867.
2. Jakubowiak AJ et al. 2010 ASCO Annual Meeting. Abstract 8003.
65
Elotuzumab Background
•
•
Elotuzumab is a humanized IgG1 mAb targeting
human CS1, a cell surface glycoprotein1,2
CS1 is highly expressed on >95% of MM cells1-3
–
–
MoA of elotuzumab is primarily through NK cellmediated ADCC against myeloma cells1,2
In a MM xenograft mouse model, the combination of
elotuzumab + lenalidomide significantly reduced
tumor volume compared with either agent alone4
•
Lower expression on NK cells
Little to no expression on normal tissues
Normal plasma cells
Plasmacytoma
600
Tumor Volume (mm3)
•
500
Lenalidomide dosing (50 mg/kg)
400
Elotuzumab (1 mg/kg) or control
IgG1 dosing
300
Control IgG1 + DMSO
Elotuzumab + DMSO
200
Lenalidomide + control IgG1
100
Elotuzumab + lenalidomide
0
Lymphoplasmacytic Myeloma cells in bone
lymphoma
marrow
14
21
28
35
Study Day
42
ADCC = antibody-dependent cellular cytotoxicity; DMSO = dimethyl sulfoxide; mAb = monoclonal antibody;
MED = maximum efficacious dose; MoA = mechanism of action; NK = natural killer.
1. Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784. Permission requested; 2. Tai YT et al. Blood. 2008;112:1329-1337;
3. Van Rhee F et al. Mol Cancer Ther. 2009;8:2616-2624; 4. Lonial S et al. ASH 2009 Annual Meeting. Abstract 432.
66
Elotuzumab + Lenalidomide + Low-Dose
Dexamethasone: Phase 1 Results
• Elotuzumab tested at 5, 10, and 20 mg/kg
– Elotuzumab-related AEs were primarily infusion-related
– 89% experienced at least 1 infusion reaction AE, no DLTs observed
and MTD not reached
Total
LenalidomideNaive
Prior Thalidomide
Refractory to Most
Recent Therapy
28
22
16
12
≥ PR, n (%)
23 (82)
21 (95)
15 (94)
10 (83)
CR/VGPR, n (%)
11 (39)
10 (45)
7 (44)
5 (42)
PR, n (%)
12 (43)
11 (50)
8 (50)
5 (42)
Total Patients, n
• Median TTP not reached at a median 12.7 months’ follow-up
• Elotuzumab saturation of CS1 binding sites in BM MM cells >80%
at both 10 (n = 1) and 20 mg/kg (n = 4)
VGPR = very good partial response; DLT = dose-limiting toxicity.
Lonial S et al. ASCO 2010 Annual Meeting. Abstract 8020; Lonial S et al. ASH 2010 Annual Meeting. Abstract
1936.
67
Efficacy
Best Response (IMWG Criteria)
Elotuzumab
10 mg/kg
Elotuzumab
20 mg/kg
Total
ORR (≥PR), n (%)
36
33 (92)
37
27 (73)
73
60 (82)
CR/stringent CR, n (%)
5 (14)
4 (11)
9 (12)
VGPR, n (%)
14 (39)
12 (32)
26 (36)
PR, n (%)
14 (39)
11 (30)
25 (34)
<PR, n (%)
3 (8)
10 (27)
13 (18)
Patients, n
• Median time to response: 1 month (range, 0.7-5.8)
• Median time to best response: 2.2 months (range, 0.7-17.5)
Lonial S et al. ASH 2011 Annual Meeting. Abstract 303.
68
Progression-Free Survival
Proportion of
Progression-Free Patients (%)
100
90
80
70
60
50
40
Median Time to Progression/Death:
Median Follow-Up:
30
10 mg/kg (n = 36): NA
10 mg/kg: 14.0 mo (range 2.6-21.2 mo)
20
20 mg/kg (n = 37): NA
20 mg/kg: 14.3 mo (range 2.1-20.5 mo)
10
0
0
No. at Risk:
10 mg/kg
20 mg/kg
36
37
1
2
3
32
29
4
5
6
30
26
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22
Months
29
23
21
19
13
14
4
4
1
0
0
0
At a median follow-up of 14.1 months, the median PFS was not reached
– PFS rate was 75% (10 mg/kg) and 65% (20 mg/kg)
Lonial S et al. ASH 2011 Annual Meeting. Abstract 303.
69
Investigator-Designated
Infusion Reactions
• Investigator-designated infusion reactions are AEs identified by
the investigator as a sign or symptom of an elotuzumab-related
infusion reaction
• AEs that occurred in ≥ 2 subjects included nausea, pyrexia, and rash
Elotuzumab
10 mg/kg
n = 36
20 mg/kg
n = 37
Total
N = 73
5 (14)
4 (11)
9 (12)
Grade 1
3 (8)
2 (5)
5 (7)
Grade 2
1 (3)
2 (5)
3 (4)
Grade 3*
1 (3) Rash
0
1(1)
Parameter, n (%)
Any AE
*There were no Grade 4 infusion reaction AEs.
Lonial S et al. ASH 2011 Annual Meeting. Abstract 303.
70
Summary
• New options and combinations are active in
relapsed/refractory disease
• Novel targets help to improve outcomes perhaps
even better than the historical use of alkylators
• Proteasome inhibitors, IMiDs, HDACs, and
antibodies will help to improve outcomes in
relapse and induction
71
Conclusion
• THERE IS NO EASY ALGORITHM FOR
MANAGING RELAPSED/REFRACTORY
MULTIPLE MYELOMA
• Patient-specific issues and prior therapy should
be used to determine choice of agents
• Use of FISH and cytogenetics can guide singleagent vs combo decision and prognosis
• New targets and agents are being explored.
Phase 3 trials are in progress
72