Moving Carfilzomib into the Frontline Setting in Multiple Myeloma :
An Irreversible Trend?
Discussion of Abstracts 8009, 8010, and 8011
Robert Z. Orlowski, Ph.D., M.D.
Director, Myeloma Section
Professor, Depts. of Lymphoma/Myeloma & Experimental Therapeutics
Principal Investigator, M. D. Anderson SPORE in Multiple Myeloma
Chair, Southwest Oncology Group Myeloma Committee
Disclosures
Grant/Research Support
Celgene Corporation, Johnson & Johnson
PRDU, Millennium Pharmaceuticals
Scientific Advisory Board
without Honoraria
Acetylon Pharmaceuticals
Scientific Advisory Board
with Honoraria
Abbott Laboratories, Bristol-Myers Squibb
Pharmaceuticals, Celgene Corporation, Centocor
Ortho-Biotech Inc., Cephalon, Millennium
Pharmaceuticals, Novartis Pharmaceuticals
Corp., Onyx Pharmaceuticals Inc.
• I will include discussion of investigational/
off-label use of carfilzomib for myeloma
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
Carfilzomib Background
• Tetrapeptide epoxyketone
• Binds the b5 & b5i subunits irreversibly
• Overcame bort resistance1
• Well tolerated in phase I2
• Active alone, and in a
number of combinations3 in
relapsed and/or refractory MM
1Kuhn
et al. Blood 110:3281, 2007. 2O’Connor et al. Clin Cancer Res. 15:7085, 2009. Alsina et al.
Submitted. 3Vij et al. Blood May 3, E-pub. Siegel et al. Submitted
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
CMP Study Overview
20
27
36
0 DLT
0 DLT
6 patients
≥ 2 DLT *
1 DLT
6 patients
≥ 2 DLT *
Up to 27mg/m²
MTD = 20
1 DLT
6 patients
≥ 2 DLT *
1 DLT
Up to 36mg/m²
MTD = 20
MTD = 27
MTD = 36
• CMP for 9 cycles of 6 weeks each
– C 20 mg/m2 iv day 1, 2 cycle 1; then 36 (MTD)
– M 9 mg/m2 po daily on days 1-4
– P 60 mg/m2 po daily on days 1-4
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
CMP vs. Other Options
• Comparisons dangerous at this stage
– Small cohort and no randomization/stratification
• 8 patients with ≤3 cycles excluded from ORR
– No information about median age, ISS stage,
cytogenetic profiles, and GEP risk
– Different study designs, with other trials (MPT,
MPR, VMP) incorporating a maintenance phase
– Authors do state that 89% ORR is very
promising compared to best MPT (76%), MPR
(80%), Rd (85%)
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
CMP vs. VMP: Response Rate
• ORR 89% for CMP in this phase I/II
– 1 CR, 14 VGPR, 16 PR, 1 MR, 2 SD, 1 PD
• Comparison made to VISTA1 (ORR 71%)
• Better benchmark is VMP phase I/II2, which
had ORR 89%
– 17 CR, 6 nCR (VGPR), 24 PR, 0 MR, 6 SD
• Duration of CMP longer (54 vs. 49 weeks)
• More doses of C given than V (72 vs. 57)
1San
Miguel et al. NEJM 359:906, 2008. 2Mateos et al. Blood 108:2165, 2006.
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
CMP vs. VMP: Response Duration
• OS
– CMP: 93.9% @ 12-month median follow-up
– VMP1: 90% @ 16-months
• EFS
– CMP: 80.7% @ 12-month median follow-up
– VMP1: 83% @ 16-months
1Mateos
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
et al. Blood 108:2165, 2006.
CMP vs. VMP: Toxicity Grade ≥3
• CMP
– Infection (15%); DVT, Afib (6% each); renal
impairment, pericardial effusion, fatigue, cardiac
failure, toxic death (3% each)
– Only 1 peripheral neuropathy (PN) at grade 1
• VMP1
– Thrombocytopenia (51%), neutropenia (43%),
PN (17%), diarrhea (16%), infection (16%)
– 16 (27%) patients received G-CSF support
1Mateos
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
et al. Blood 108:2165, 2006.
CYCLONE Study Overview
Agent
Dose Level
Day
Carfilzomib
See Phase I and II dosing
(15-27 mg/m2)
1, 2, 8, 9, 15, 16 (of
every 28-day cycle)
Thalidomide
100 mg
1-28
300 mg/m2
1, 8, 15
40 mg
1, 8, 15, 22
Cyclophosphamide
Dexamethasone
• Rationale
– Build on international standard CTD
1
– Add new PI with less
vs.
neuropathy to front-line
– Save lenalidomide & bortezomib (?) for relapse
1Disclosure:
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
I own no stock in Time Warner.
CYCLONE Outcomes
• ORR 96% in phase II after 4 cycles
– 7 CR, 11 VGPR, 5 PR, 1 MR; 75% ≥VGPR
– 24 responses/27 patients reported (VGPR 67%)
– ECOG 0 in 74%, ISS I in 43%
– No information about molecular risk
– Need long-term follow-up (median 8.2 months)
• Additional dose levels being explored with
carfilzomib at >20 mg/m2
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
CYCLONE Efficacy Comparators
• CTD
– Transplant eligible patients
• ORR 82.5%, CR 13%, ≥VGPR 43% (n=555)1
– Transplant ineligible patients
• ORR 63.8%, CR 13.1%, ≥VGPR 30% (n=426)2
• CyBorD
– Mixed patients (x 4 cycles)
• ORR 88%, CR/nCR 46%, ≥VGPR 61% (n=33)3
1Morgan
et al. Haematologica 97:442, 2012. 2Morgan et al. Blood 118:1231, 2011. 3Reeder et al.
Leukemia 23:1337, 2009.
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
Efficacy Comparators II
• VMPT
– Transplant ineligible patients (also + VT maint.)
• ORR 89%, CR 38%, ≥VGPR 67% (n=250)1
• VDCmod vs. VDCR
– Mixed population (x 4 cycles)
• ORR 100% vs. 88% (n=17 vs. n=48)
• CR 47% vs. 25%; VGPR 53% vs. 58%2
• If 4 drugs are not better than 3, why not use
CarCyDex and eliminate Thal altogether?
1Palumbo
et al. J Clin Oncol 28:5101, 2010. 2Kumar et al. Blood 119:4375, 2012.
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
CRd Study Overview
CRd
Induction
Transplanteligible and
-ineligible CRd Cycles 1–4
patients
CRd Cycles 5–8
CRd
Maintenance
CRd Cycles 9–24
Tran spl ant-eligible
≥PR
ASCT
•Cycles 1–8
• CFZ Days 1–2, 8–9, 15–16 at assigned doses
• LEN 25 mg Days 1–21
• DEX 40 mg weekly Cycles 1-4, 20 mg weekly Cycles 5–8
• CFZ on Days 1–2 and 15–16 only
• CFZ, LEN, DEX at last best tolerated doses
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
LEN Cycles 25+
Until disease progression or
unacceptable toxicity
Stem cell collection
•Cycles 9–24
Lenalidomide
(off protocol)
Efficacy & Durability
Best Response
100
•nCR
sCR
80
78
60
Patients (%)
40
62
42
67
45
20
0
Overall
4+ Cycles
8+ Cycles
n=53
Median 12 cycles
(range 1 Š25)
n=49
Median 13 cycles
(range 4 Š25)
n=36
Median 16 cycles
(range 8 Š25)
PFS 97% @ 12 months
PFS 92% @ 24 months
N= 53; median 12 cycles (range 1–25)
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
61
Efficacy Comparators
• RVD
– ORR 100%, ≥VGPR 67%1
– PFS @ 18 mos. was 75% (median of 10 cycles
vs. ? for CRd)
– 8 cycles CRd is more therapy than 8 of RVd
•
•
•
•
32 weeks vs. 24 weeks
CRd has more proteasome inhibitor doses (48 vs. 32)
CRd has more lenalidomide (168 days vs. 112 days)
CRd has less dexamethasone (960 mg vs. 1280 mg)
1Richardson
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
et al. Blood 116:679, 2010.
Comparators II
• CRd
– High rate of sCR (CR + normal serum free light
chains) of 61% after 8+ cycles
• As sCR is a relatively new parameter, it has not been
reported in RVd1
• sCR may not have better outcome than CR2
– 20/22 patients (91%) with suspected CR had no
MRD by flow immunophenotyping
• Immunophenotypic CR associated with prolongation of
TTP and EFS compared to less rigorous CR
1Richardson
et al. Blood 116:679, 2010. 2Paiva et al. J Clin Oncol. 29:1627, 2011.
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
Conclusions
• Up-front combinations with carfilzomib are
showing attractive response rates
• Depth of response (CR, sCR) seems
improved in some studies, though longer f/u
is needed
• Tolerability may be improved, especially with
less neuropathy, but data from comparisons
are needed with sc ± weekly bortezomib
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.
Future Directions
• Phase III studies needed to determine role
of these attractive regimens in our armamentarium for newly diagnosed patients
• Trials must be performed in a risk-adapted
fashion given large difference in outcomes
for patients with standard vs. high risk
– ECOG E1A11: RVd vs. CRd for standard
– SWOG S1211: RVd vs. RVd/Elo for high risk
PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.