Should Alkylators be used Upfront in Transplant-Ineligible Patients? NO!! Lymphoma-Myeloma October 2013 - PowerPoint PPT Presentation

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Should Alkylators be used Upfront in Transplant-Ineligible Patients? NO!! Lymphoma-Myeloma October 2013

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Should Alkylators be used Upfront in Transplant-Ineligible Patients? NO!! Lymphoma-Myeloma October 2013 Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida – PowerPoint PPT presentation

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Title: Should Alkylators be used Upfront in Transplant-Ineligible Patients? NO!! Lymphoma-Myeloma October 2013


1
Should Alkylators be used Upfront in
Transplant-Ineligible Patients? NO!!
Lymphoma-Myeloma October 2013
Joseph Mikhael, MD, MEd, FRCPC, FACP Staff
Hematologist, Mayo Clinic Arizona
2
Objectives
  1. Review the emerging data regarding replacing MP
    as backbone in upfront therapy
  2. Provide practical advice as to initiating therapy
    in older patients with myeloma
  3. Unequivocally defeat my friend Antonio in this
    debate ?
  4. Concede that cyclophosphamide may be an exception
    to this general rule

3
Summary Points Why Melphalan is no longer
standard of initial care in elderly patients
  1. Novel agents are equivalent if not superior to
    MPnovel agent
  2. MP results in greater short term toxicity
  3. As survival is extended in myeloma, using
    melphalan upfront is not desirable due to marrow
    toxicity
  4. Melphalan can lead to increased second primary
    malignancies

4
mSMART 2.0 Classification of Active MM
Standard-Risk 60
High-Risk 20
Intermediate-Risk 20
  • FISH
  • Del 17p
  • t(1416)
  • t(1420)
  • GEP
  • High risk
  • signature
  • All others including
  • Hyperdiploid
  • t(1114)
  • t(614)
  • FISH
  • t(414)
  • Cytogenetic Deletion 13 or hypodiploidy
  • PCLI gt3

3 years 4-5 years
8-10 years
Mikhael et al Mayo Clinic Proceedings April 2013
5
mSMART Off-Study Transplant Ineligible
Intermediate Risk
Standard Risk
High Risk
MP weekly Bortezomib or weekly CyBorD
VRd
Rd
Bortezomib maintenance
Observation
Mikhael et al Mayo Clinic Proceedings April 2013
6
Argument 1
  • Novel agents are equivalent if not superior to
    MPnovel agent

7
Newly Diagnosed, Patients SCT Ineligible
MPT1 N 129 VMP2 N 337 MPR3 N 153 MPR-R4 N 152 VTP5 N 130
CR 16 30 11 16 27
gt VGPR 29 Not reported 33 32 37
gt PR 69 71 68 77 81
PFS 21.8 mo TTP 24.0 mo 14 mo 31 mo 23 mo
Median follow-up 31.8 mo 36.7 mo 25 mo 25 mo 22 mo
MPT melphalan, prednisone, thalidomide VMP
bortezomib, melphalan, prednisone MPR
melphalan, prednisone, lenalidomide MPR-R MPR
with maintenance lenalidomide VTP bortezomib,
thalidomide, prednisone.
1Palumbo A, et al. Blood. 20081123107-3114
2Mateos MV, et al. Blood. 2009114(22). Abstract
3859 3,4Palumbo A, et al. Blood. 2010116(21).
Abstract 622 and Abstract 566 5Mateos MV, et
al. Blood. 2009114(22). Abstract 3.
8
Primary Study Schema
lenalidomide plus RD versus lenalidomide plus Rd
in newly diagnosed MM
Rajkumar et al
9
BEST RESPONSE gt PR
RD n Rd n Odds Ratio Fisher's Exact
Overall 81.3 214 70.2 208 1.85 p0.009
lt 65 85.4 103 66.0 103 3.02 p0.002
gt 65 77.5 111 74.3 105 1.19 p0.634
gt 70 74.6 71 73.8 65 1.04 p1.000
gt 75 77.8 36 70.4 27 1.47 p0.566
Same observations with VGPR except age gt 70
42.3 vs 47.7
10
Results Second Interim Analysis RD vs. Rd
RD Rd
CR PR 79 68
1 year OS 87 96
Grade 3 or worse AE 52 35
RD did not result in superior TTP, PFS, or OS
compared to Rd
OS at 1-year was significantly better with Rd
than RD, resulting in early closure of the trial
Rajkumar et al, 2010.
11
Overall Survival-ITT
Age gt 70
Age lt 65
Age gt 65
Age gt 75
Age gt 65 yrs


Status RD N223 () Rd N220 () Total N443
Treatment End by Mandatory Crossover Treatment End by Mandatory Crossover Treatment End by Mandatory Crossover Treatment End by Mandatory Crossover Treatment End by Mandatory Crossover Treatment End by Mandatory Crossover
Yes 195 (87.4) 169 (76.8) 364
No 28 (12.6) 51 (23.2) 79
12
Survival Rate by Age
N 12 month survival probability (95CI) 24 month survival probability (95CI)
Age lt65
Len-High Dex 104 0.92 (0.87-0.98) 0.86 (0.79-0.93)
Len-Low Dex 108 0.96 (0.93-1.00) 0.92 (0.87-0.97)
Age 65
Len-High Dex 119 0.84 (0.78-0.91) 0.72 (0.64-0.81)
Len-Low Dex 114 0.95 (0.91-0.99) 0.85 (0.79-0.92)

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Larocca A, et al. Gr. Emat. Milano 2012
17
Conclusion 1
  • MP is not necessary
  • Lenalidomide-dexamethasone and bortezomib-dexameth
    asone are effective and viable options

18
Argument 2
  • MP results in greater short term toxicity

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Conclusion 2
  • 3 drug regimens that include melphalan are more
    toxic (and not necessarily more effective)
  • Dose reduction is critical in the elderly

25
Argument 3
  • As survival is extended in myeloma, using
    melphalan upfront is not desirable due to marrow
    toxicity

26
Multiple Myeloma 1971-2006 n2,981
Plt0.001
Survival, med 44.8 mo
Proportion surviving
Survival, med 29.9 mo
Diagnosis after 1996
Diagnosis during/ before 1996
Time from diagnosis (months)
Kumar et al Blood 1112516, 2008
CP1315995-1
27
Multiple Myeloma Mayo Patients
2006-2010
66
P lt 0.0001
47
2001-2005
S. Kumar, 2012
28
Argument 4
  • Melphalan can lead to increased second primary
    malignancies

29
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33
The NEW CyBorD
  • All three drugs given weekly
  • Cyclophosphamide 300mg/m2 PO
  • Bortezomib 1.5 mg/m2 IV or SQ
  • Dexamethasone 40mg PO
  • We consider one cycle a 4 week course
  • No week off
  • Less neuropathy, more convenience, equal efficacy
  • Always give viral prophylaxis
  • Comment I see CyBorD as a slight modification
    to VMP

34
Summary Points Why Melphalan is no longer
standard of initial care in elderly patients
  1. Novel agents are equivalent if not superior to
    MPnovel agent
  2. MP results in greater short term toxicity
  3. As survival is extended in myeloma, using
    melphalan upfront is not desirable due to marrow
    toxicity
  4. Melphalan can lead to increased second primary
    malignancies

35
Quote ASCO 2013 Dr. Antonio Palumbo
  • Gli Americani avevano ragione non dobbiamo
    usare melphalan come terapia iniziale nei
    pazienti anziani
  • The Americans were right we should not use
    melphalan upfront in elderly patients
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