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Transcript of Rafael Fonseca MD Mayo Clinic Multiple Myeloma 2012; Update Scottsdale, Arizona Rochester, Minnesota...
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Rafael Fonseca MDMayo Clinic
Multiple Myeloma 2012;Update
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida
Mayo Clinic College of MedicineMayo Clinic Comprehensive Cancer Center
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Disclosures
• Consulting: AMGEN, Genzyme, BMS, Otsuka, Celgene, Medtronic, Lilly, Onyx.
• Millennium
• Speakers Bureaus: None
• Research: Cylene, Proteolix
• Patent for FISH based prognostication in MM
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Clinical Features
• Calcium elevation
• Renal disease
• Anemia
• Bone disease
• …and other constitutional
Smith. Br J Haematol. 2005;132:410.
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Importance of progression events
4
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Renal Metabolism of FLCs
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0.1
1
10
100
1000
10000
Lig
ht
chai
n c
on
cen
trat
ion
(m
g/L
)
SPE
CZE IFE
Total k & l
Normal range in serum
FLC
UPE
Analytical sensitivity of laboratory methods for detection of FLCs
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Katzmann, Clin Chem 2002; 48: 1437 - 1444
sFLCs published normal range
0.1
1
10
100
1000
10000
100000
0.1 1 10 100 1000 10000 100000
Serum Kappa FLC (mg/L)
Se
rum
La
mb
da
FLC
(m
g/L
)
Normal sera
Renal impairment(non-MG)
Bradwell, Lancet 2003; 361: 489-491
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sFLCs in LCMM and NSMM
Drayson Blood 2001; 97: 2900 – 2902
Normal sera
Kappa LCMM
Lambda LCMM
NSMM
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MTCG. J Clin Oncol 1998; 16:3832
Treatment of Myeloma
42% at 3 years
MP era 2008
93% at 3 years
Menon S. Cancer 112:1522-1528
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Spanish Long Term
Blood 2011 blood-2011-01-332320 10
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Transplant Outcomes
11Reeder et al, Leukemia 2009, 23:1337-41
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Minimal Residual Disease
Ladetto M, et al. ASH 2009. Abstract 960.
PFS in PCR-negative patients
0 10 20 30 40 50 60 70 80 900
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
PCR POS
PCR NEG
P < .05
months
Obs
erve
d m
argi
nal m
edia
ns o
f ln
PC
R v
alue
s
Relapse (13 patients)
No relapse (25 patients)
DIA ASCT VTD-2 VTD-4 6 m 12 m 18 m 24 m 30 m
Obs
erve
d m
argi
nal m
edia
ns o
f ln
PC
R v
alue
s
Relapse (13 patients)
No relapse (25 patients)
Obs
erve
d m
argi
nal m
edia
ns o
f ln
PC
R v
alue
s
Relapse (13 patients)
No relapse (25 patients)
Relapse (13 patients)
No relapse (25 patients)
DIA ASCT VTD-2 VTD-4 6 m 12 m 18 m 24 m 30 mDIA ASCT VTD-2 VTD-4 6 m 12 m 18 m 24 m 30 m
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Genomics and Precision Medicine
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Submarine
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REAL TIME REPORT GENERATED FOR PATIENT AND TREATING PHYSICIAN
N OF 1
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• CCND1 2%
• BRAF 4%
• DIS3 (RPP44) 11%
• FAM46C 13%
• XBP1 4%
• LRRK2 6%
• IRF 6%
• PRDM1 6%
• Known; ras (50%), NF-kB (37%), p53 (8%)
• Protein translation 42%
• Histone modifying enzymes (lead HOXA9)
• Fibrin clot formation 16%
Nature 24 March 2011, 471:467
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Study population stratified according
to cytogenetic abnormalities232
pts
no cytogenetic
abnormalities + del
(13q)
+ t(11;14)
188 pts(80%)
t(4;14) ± t(14;16)
+ del(17p)
44 pts(19%)
t(4;14)±del(13q
)
17 (7%)
del(17p)
±del(13q)
21(9%)
both
3 (1%)
t(14;16)
3 (1%)
Standard-risk High-risk
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Overall survival according
to cytogenetic abnormalities
50454035302520151050
1.0
0.8
0.6
0.4
0.2
0.0
Pro
po
rtio
n o
f p
ts
Time in months from 1st randomization
Standard risk: NR
High risk: 38m
HR: 2.3, 95% IC: 1.4-4.0
p=0.001
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EFS and OS; t(4;14) VD (n = 106) vs VAD (n = 98)
Avet-Loiseau H et al. JCO 2010;28:4630-4634
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EFS and OS; VD Treated t(4;14) (n = 106) vs not (n = 401)
Avet-Loiseau H et al. JCO 2010;28:4630-4634
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Avet-Loiseau H et al. JCO 2010;28:4630-4634
No t(4;14) Bortezomib treated
t(4;14) Bortezomib treated
t(4;14) VAD treated
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High Risk in Len Treated Patients
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Lenalidomide maintenance on PFS of t(4;14)0
.00
0.2
50
.50
0.7
51
.00
0 6 12 18 24 30 36 42
Placebo Revlimid
p<.0001
IFM 2005-02 trial: general results for PFS
0.0
00
.25
0.5
00
.75
1.0
0
0 6 12 18 24 30 36 42
Placebo Revlimid
p<.001
PFS for patients with del(13)
0.00
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36 42
Placebo Revlimid
p<.02
PFS for patients with del(17p) > 60%
0.00
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36 42
Placebo Revlimid
p<.04
PFS for patients wit t(4;14)
del13
del17p t(4;14)
Avet-Loiseau ASH 2010
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Carfilzomib and PX-171-004
• Carfilzomib is a selective tetrapeptide epoxyketone proteasome inhibitor that displays potent and sustained proteasome inhibition.
• The high degree of selectivity of carfilzomib may account for its improved tolerability profile: – In early clinical studies, carfilzomib has not been associated with
dose-limiting peripheral neuropathy (PN).
• PX-171-004 is an ongoing multicenter, non-randomized, open-label, single-arm phase 2 trial of single-agent carfilzomib in patients with R/R MM who have received 1–3 prior lines of therapy.
K Stewart et al ASCO Abstract 8026
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Study Design and Treatment
• Bortezomib-naïve patients (N=129) were enrolled in 2 sequential dose cohorts.
– In Cohort 1, patients received carfilzomib 20 mg/m2 IV on Days 1, 2, 8, 9, 15, and 16 every 28 days, for up to 12 cycles.
– In Cohort 2, patients received a stepped-up, dose-escalating regimen of carfilzomib 20 mg/m2 for Cycle 1 followed by carfilzomib 27 mg/m2 for all subsequent treatment cycles.
– Dexamethasone 4 mg was administered prior to carfilzomib in Cycle 1 only to ameliorate a potential “first dose” effect (including fever, chills, rigors, and dyspnea).
• Patients completing all 12 cycles were eligible to enroll in an extension study (PX-171-010).
K Stewart et al ASCO Abstract 8026
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Significant Responses‡ in BTZ-naïve Patients
*Data cut-off date 9 February 2011†2 patients (3%) in Cohort 2 were excluded on the basis of missing baseline or post-baseline disease assessments.‡Responses confirmed by Independent Review Committee
Best response(N=127)
Cohort 1 20 mg/m2
(N=59)n (%)
Cohort 2†
20/27 mg/m2
(N=68)n (%)
CR 2 (3) 0 (0)
VGPR 8 (14) 18 (26)
PR 15 (25) 17 (25)
MR 10 (17) 8 (12)
SD 13 (22) 10 (15)
PD 7 (12) 11 (16)
NE 4 (7) 4 (6)
• Significant response rates were observed in both cohorts
ORR= 42% ORR= 51%
CBR= 63%CBR= 59%
K Stewart et al ASCO Abstract 8026
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Substantial Duration of Response Observed for Cohorts 1 and 2*
*Data cut-off date 9 February 2011 K Stewart et al ASCO Abstract 8026
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Similar Incidence and Severity of AEs Between Cohorts
• There were no discontinuations of treatment due to peripheral neuropathy.
• In no case were any toxicities (any grades) >2% higher in Cohort 2 than in Cohort 1; in general they were either similar or lower
• cumulative toxicities has been observed in patients continuing on extended carfilzomib treatment (PX-171-010).
K Stewart et al ASCO Abstract 8026
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Pomalidomide in Len Treated PatientsPatient Characteristics
J Mikhael et al ASCO Abstract 8067
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Response rate on Pomalidomide Despite Prior Treatment with Lenalidomide
J Mikhael et al ASCO Abstract 8067
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MRC Myeloma IX—Analysis Schematic for ZOL vs CLO
Endpoints (ZOL vs CLO)Primary: PFS, OS, and ResponseSecondary: SREs (time to first SRE, SRE incidence) and SafetySREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions, or the appearance of new osteolytic bone lesions.
N = 1,960Patients with newly
diagnosed MM (stage I, II, III)
Clodronate (1,600 mg/d PO) + intensive or non-intensive chemotherapy
(n = 979)
Zoledronic acid (4 mga IV q 3-4 wk) + intensive or non-intensive chemotherapy
(n = 981)RANDOMISATION
Bisphosphonate treatment continued at least until disease progression
G Morgan et al ASCO Abstract 8010
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MRC Myeloma IX—ZOL Significantly SREs vs CLO in the Overall Population
Abbreviations: CLO, clodronate; HR, hazard ratio; SRE, skeletal-related event; ZOL, zoledronic acid.
35.3%
27.0%
• ZOL reduced the risk of SREs by 26% vs CLO (HR = 0.74; P = .0004)
36 423024181260
0
10
20
30
40CLO
ZOL
Pa
tie
nts
wit
h a
n S
RE
, %
Time from randomisation, months
138112
9774
201173
284256
390337
506465
663629
981979
ZOLCLO
Patients at risk, n
G Morgan et al ASCO Abstract 8010
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ZOL Significantly OS vs CLO in Patients With Bone Disease at Baseline (n = 1,350)
50
60
70
80
90
100
40
30
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n e
stim
ate
OS
, %
pat
ien
ts
20
10
0
0 1 2 3 4 5 6
668682
544534
447437
292271
165143
6453
30
Survival, years since initial randomisation
Clodronate (n = 682)
Zoledronic acid (n = 668)
P = .0107
HR: 0.82 (95% CI: 0.70, 0.96)
+ Censored
ZOLCLO
Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; ZOL, zoledronic acid. G Morgan et al ASCO Abstract 8010
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Phase III IFM 2005-02: Lenalidomide as Consolidation/Maintenance Post-ASCT
First-line
ASCT < 65 years
Lenalidomide: 25 mg/d Days 1–21/month2 months
Primary end point: PFS
≤ 6 monthsNo PD
N = 614Lenalidomide: 10–15 mg/duntil relapse
Lenalidomide: 25 mg/d Days 1–21/month2 months
Placebo until relapse
Consolidation Maintenance
Attal et al, 2009.
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Lenalidomide maintenance on PFS of t(4;14)0
.00
0.2
50
.50
0.7
51
.00
0 6 12 18 24 30 36 42
Placebo Revlimid
p<.0001
IFM 2005-02 trial: general results for PFS
0.0
00
.25
0.5
00
.75
1.0
0
0 6 12 18 24 30 36 42
Placebo Revlimid
p<.001
PFS for patients with del(13)
0.00
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36 42
Placebo Revlimid
p<.02
PFS for patients with del(17p) > 60%
0.00
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36 42
Placebo Revlimid
p<.04
PFS for patients wit t(4;14)
del13
del17p t(4;14)
Avet-Loiseau ASH 2010
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D-S Stage 1-3, < 70 years> 2 cycles of induction Attained SD or better 1 yr from start of therapy> 2 x 106 CD34 cells/kg
Placebo
Lenalidomide*10 mg/d with
↑↓ (5–15 mg)
RestagingDays 90–100
Registration
CALGB 100104 Schema
CRPRSD
Patient stratification based on diagnostic -2M level and prior thalidomide and lenalidomide use during Induction
Mel 200
ASCT
* provided by Celgene Corp, Summit, NJ
Randomization
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ITT Analysis with a Median Follow-up from transplant of 18 months P < 0.0001
CALGB 100104, follow up to study un-blinding
Median TTP: 21.9 mo
Median TTP: 39.6 mo
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Median follow-up of 28 monthsP = 0.018
CALGB 100104, follow up to 04/17/2011
23 deaths in the lenalidomide arm and 39 deaths in the placebo arm
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1
MP
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
PBO: days 1-21
MPR
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21Placebo
Placebo
Phase III Study Schema
MPR-R
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
RA
ND
OM
ISA
TIO
N
Double-Blind Treatment Phase
DiseaseProgression
Continuous LenalidomideTreatment
Lenalidomide
(25 mg/day) +/-
Dexamethasone
Open-Label Extension Phase
N = 459, 82 centers in Europe, Australia, and Israel
Stratified by age (≤ 75 vs > 75 years) and stage (ISS I/II vs III)
10 mg/daydays 1-21
Cycles (28-day) 1-9 Cycles 10+
M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System.
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1
Progression-Free Survival*All Patients
60% Reduced Risk of Progression
Time (months)
Pat
ien
ts (
%)
HR 0.398 P < .0000001
Median PFS
MPR-R 31 months
MPR 14 months
MP 13 months
Median PFS
MPR-R 31 months
MPR 14 months
MP 13 months
Median follow-up 25 months
0 5 10 15 20 25 30 35 400
25
50
75
100
0 5 10 15 20 25 30 35 400
25
50
75
100
0 5 10 15 20 25 30 35 400
25
50
75
100
*Analysis based on data up to May 2010
HR 0.804P = .153
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Other Notable Abstracts at ASH
J Mikhael et al ASCO Abstract 8067
• MLN9708, the oral proteasome inhibitor
• Marizomib (NPI-0052)
• BT062 the antibody-drug conjugate
• Phase 2 study of elotuzumab-lenalidomide and low dose Dex
• Vorinostat plus bortezomib as Salvage therapy
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Standard Risk MM SCT
16 weeks of weekly CyBORD with
supportive care
SC collection and SCT
Minimize gap between Rx end and SCT
Len maintenance(+/- Dex at start)
Start at day 100
High Risk MM SCT
16 weeks of weekly RVD with
supportive care
SC collection and SCT
Minimize gap between Rx end and SCT
Len maintenance(+/- Dex at start)
Start after CyBORD
16 weeks of CyBORD
consolidation
Bisphosphonate per Mayo; RNE responsibility
Bisphosphonate per Mayo; RNE responsibility
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Sequencing of Treatments
Maintenance approach
Biochemical relapse approach
Clinical relapse approach