Moving Carfilzomib into the Front-line Setting in Multiple

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Moving Carfilzomib into the Front-line 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
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Disclosures

• I will include discussion of investigational/
  off-label use of carfilzomib for myeloma

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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 1103281, 2007. 2OConnor et
al. Clin Cancer Res. 157085, 2009. Alsina et al.
Submitted. 3Vij et al. Blood May 3, E-pub. Siegel
et al. Submitted
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CMP Study Overview
20
27
36
0 DLT
0 DLT
6 patients
6 patients
6 patients
1 DLT
1 DLT
1 DLT
2 DLT
2 DLT
2 DLT
Up to 27mg/m²
Up to 36mg/m²
MTD 27
MTD 36
MTD 20
MTD 20

• 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

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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)

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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 359906, 2008. 2Mateos
et al. Blood 1082165, 2006.
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CMP vs. VMP Response Duration

• OS
• CMP 93.9 _at_ 12-month median follow-up
• VMP1 90 _at_ 16-months
• EFS
• CMP 80.7 _at_ 12-month median follow-up
• VMP1 83 _at_ 16-months

1Mateos et al. Blood 1082165, 2006.
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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 et al. Blood 1082165, 2006.
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CYCLONE Study Overview

• Rationale
• Build on international standard CTD
• Add new PI with less
• neuropathy to front-line
• Save lenalidomide bortezomib (?) for relapse

1
vs.
1Disclosure I own no stock in Time Warner.
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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 gt20 mg/m2

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CYCLONE Efficacy Comparators

• CTD
• Transplant eligible patients
• ORR 82.5, CR 13, VGPR 43 (n555)1
• Transplant ineligible patients
• ORR 63.8, CR 13.1, VGPR 30 (n426)2
• CyBorD
• Mixed patients (x 4 cycles)
• ORR 88, CR/nCR 46, VGPR 61 (n33)3

1Morgan et al. Haematologica 97442, 2012.
2Morgan et al. Blood 1181231, 2011. 3Reeder et
al. Leukemia 231337, 2009.
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Efficacy Comparators II

• VMPT
• Transplant ineligible patients (also VT maint.)
• ORR 89, CR 38, VGPR 67 (n250)1
• VDCmod vs. VDCR
• Mixed population (x 4 cycles)
• ORR 100 vs. 88 (n17 vs. n48)
• CR 47 vs. 25 VGPR 53 vs. 582
• If 4 drugs are not better than 3, why not use
  CarCyDex and eliminate Thal altogether?

1Palumbo et al. J Clin Oncol 285101, 2010.
2Kumar et al. Blood 1194375, 2012.
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CRd Study Overview
CRd Induction
CRd Maintenance
Lenalidomide (off protocol)
Transplant-eligible and -ineligible patients
LEN Cycles 25
CRd Cycles 924
CRd Cycles 14
CRd Cycles 58
Until disease progression or unacceptable toxicity
Tran spl ant-eligible
PR
ASCT
Stem cell collection

• Cycles 18
• CFZ Days 12, 89, 1516 at assigned doses
• LEN 25 mg Days 121
• DEX 40 mg weekly Cycles 1-4, 20 mg weekly Cycles
  58
• Cycles 924
• CFZ on Days 12 and 1516 only
• CFZ, LEN, DEX at last best tolerated doses

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Efficacy Durability
Best Response
Patients ()
PFS 97 _at_ 12 months PFS 92 _at_ 24 months
N 53 median 12 cycles (range 125)
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Efficacy Comparators

• RVD
• ORR 100, VGPR 671
• PFS _at_ 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 et al. Blood 116679, 2010.
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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 116679, 2010. 2Paiva et
al. J Clin Oncol. 291627, 2011.
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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

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Future Directions

• Phase III studies needed to determine role of
  these attractive regimens in our arma-mentarium
  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