Treatment of Transplant Ineligible/Elderly MM Patients

1
Treatment of Transplant Ineligible/Elderly MM
Patients
Myelomacenter.org run9001_at_med.cornell.edu

• Ruben Niesvizky
• Department of Medicine, Division of
  Hematology/Oncology, Weill-Cornell Medical
  College / New York Presbyterian Hospital, New
  York, NY, USA

2
Disclosures

• Speakers bureau Celgene, Millennium, Onyx

3
Case

• 65 year-old Hispanic male
• Presents to emergency room with chest pain,
  fatigue found with
• Creatinine 5.0
• Hemoglobin 8.9
• Multiple lytic lesions
• Total urine protein 20 gm/24 hr
• UPEP 19.4 gms kappa light chain
• SPEP 0.1 monoclonal peak
• ß2M 15.0
• BM 50 plasma cells

4
Case Discussion

• As you discuss with him his disease and his
  prognosis, he is concerned that his age precludes
  him from aggressive therapy. You advise him
• He is a young person with lots of experience,
  and his age should not preclude him from
  receiving aggressive therapy with the intent of
  changing the natural history of his disease
• Patients over the age of 65 should not be
  considered for aggressive therapies

5
The Elderly Patient
The median age at diagnosis is 70 years

• Nearly half of multiple myeloma patients are
  considered elderly
• Current distinction of elderly based on
  transplant eligibility (European and North
  American trials)
• Patients under 65 years
• of age, 35
• Older patients from 65 to 75 years
• of age, 28
• Elderly patients over 75, 37

.
Palumbo A, et al. Hematology Am Soc Hematol Educ
Program. 2009566-577. Ferlay J, et al. GLOBOCAN
2002 Cancer Incidence, Mortality and Prevalence
Worldwide. IARC CancerBase No. 5 Version 2.0.
Lyon IARC Press 2004. Ries LAG, et al.
National Cancer Institute. SEER Cancer Statistics
Review. Source SEER 13. Accessed August 24, 2010
at http//seer.cancer.gov/faststats
6
Myeloma 5-year Relative Survival Rates
25.2
42.9
lt 65 years
gt65 years
SEER 1995-2001
7
Novel Agent Limitations in the Aging Population
Median OSlt65 60 m Median OSgt65 32 m
Kumar et al. Blood 2007
8
Treatment of Elderly MM Patients Leading Questions

• What is the goal of treatment (does CR matter)?
• What is the best induction treatment?
• Is it possible to individualize the treatment?
• Can novel drugs improve outcome

9
Treatment of Elderly MM Patients Leading Questions

• What is the goal of treatment (does CR matter)?
• What is the best induction treatment?
• Is it possible to individualize the treatment?
• Can novel drugs improve outcome

10
CR in Non-Transplant Setting
van de Velde et al. Haematologica 2007
Mean 3.6 Mean 3.6 Mean 3.6
?CR/nCR OS ?OS
10 35m 12.6m
10 50m 18m

• 5 of 13 studies failed to show association
  primarily due to the confounding effect of a
  therapy that generates high CR and is
  simultaneously too toxic
• Two polarizing impact of a therapy on survival
  (higher CR leading to longer survival vs higher
  toxicity leading to shorter survival) confounds
  analysis

• Medline/OVID search from 1980 Mar 2008
• 13 studies (4396 patients) meeting the criteria
  randomized comparative trials in newly diagnoses
  MM reporting CR or CR/nCR and survival (either
  median survival or survival rate)
• Percent improvement in survival for each percent
  increase in the CR/nCR rate was calculated for
  each study

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Hematologic CR Correlates with Long-term PFS and
OS in Elderly Patients Treated with Novel Agents

• Retrospective analysis 3 randomized European
  trials of GIMEMA and HOVON groups (N1175)
• First-line treatment
• MP (n332), MPT (n332), VMP (n257), VMPT-VT
  (n254)
• Significant benefit also seen when analysis is
  restricted to patients gt75 years old

PFS
OS
CR
CR
VGPR
Probability
Probability
VGPR
PR
PR
Plt0.001
Plt0.001
Gay et al. Blood 2011 117(11)3025-31
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The Better the Quality of the Response the Longer
the Survival (Immunophenotypic CR) GEM2005gt65y
PFS
Immunophenotypic CR 90 at 3y Stringent
CR 38 at 3y Conventional CR 57 at 3y PR
(70 reduction) 28 at 3y
100
80
60
40
20
P 0.001
0
60
50
40
30
20
10
0
Paiva et al J Clin Oncol. 201129(12)1627-33.
Months
13
Sequential Approach NDMM Patients
Transplant MEL100 two courses
Induction PAD four 21-day courses
Consolidation Len-Pdn four 28-day courses
Maintenance Len until progression
Median follow-up 66 months Median age
70 years
PFS
OS according response
PFS according response
VGPR
months
months
months
Gay F, et al. Gr. Emat. Milan 19 November 2012
PAD, bortezomib-pegylated doxorubicin-dexamethason
e MEL100, Melphalan100 mg/m2 Len-Pdn,
lenalidomide-prednisone Len, lenalidomide PFS,
progression-free survival OS, overall survival
CR, complete response VGPR, very good partial
response PR, partial response NDMM, newly
diagnosed multiple myeloma
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CR Should Be an Important Objective in Elderly MM
Patients

• Important Aim of Treatment
• Achievement of high-quality, sustained CR
  balanced with acceptable toxicity

15
Treatment of Elderly MM Patients Leading Questions

• What is the goal of treatment (does CR matter)?
• What is the best induction treatment?
• Is it possible to individualize the treatment?
• Can novel drugs improve outcome

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THALIDOMIDE
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MPT vs. MP Efficacy in Newly Diagnosed Elderly
Myeloma Patients

• 3 trials (IFM991, IFM012, HOVON3). gt RR,
  PFS OS
• 2 trial (GIMEMA4, TURKISH5). gt RR, PFS
• 1 trial (Nordic6 ).. gt RR

RR 59 vs. 37 (gt22) CR 10
vs. 2,5 (gt8 ) PFS 20,4 vs. 15
m ( 6 m) HR 0,67 OS 39,3 vs. 32,7
m (gt6 m)HR 0,83

• Thal maintenance in Italian, Nordic, Hovon
• Facon et al. Lancet 200737012091218 2. Hulin
  et al. JCO 2009 27(22)3664-70 3. Wijermans
  JCO 2010 28 3160-6 4. Palumbo et al. Blood
  2008 112 31073114 5. Beksac M et al. Eur J
  Haematol 2010 8616-22 6. Waage et al Blood
  2010116(9)1405-12 Fayers PM et al. Blood 2011
  118(5) 1239-47

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MPT vs. MP Toxicity
MPT MP
Grade 3-4 hematologic Aes 32 29
Grade 3-4 non-hematologic Aes 40 18
-Infection 13 9
-Peripheral Neuropathy 15 3
-Deep Venous Thrombosis 6 2
-Toxicity-related discontinuations 35 5
Appropriate thromboprophylaxis is required p
of significant value
Palumbo A. Haematologica 2012 Epub ahead on
August 8
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Other Thalidomide-based Combinations in
Front-line
Study
Results
Reference
  CTDa MP
PR 64 33
CR 13 3
OS 33m 31m
Morgan et al. Blood 2011 118(5) 1231-8
Phase 3 CTDa vs MP
  Thal/Dex MP
PR 73 42
TTP 21m 29m
OS 41m 49m
Phase 3 Thal/dex vs MP
Ludwig et al. Blood,2009 1133435-43

• In patients gt 75 years, OS longer with MP (41 vs
  20m)
• In patients lt75 years, similar OS
• Higher mortality during 1st y with thal/dex vs MP
  (28 vs 16, p0.02)

Thal 200 mg daily Dex 40 mg days 1-4 9-12
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LENALIDOMIDE
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Lenalidomide(R) /- MP MPR-R vs. MPR vs. MP

• Phase III Study Scheme N459 patients gt 65years

Cycles (28-day) 1-9
Cycles 10
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
RANDOMISATION
Diseaseprogression
LenalidomideContinued Tx
Lenalidomide (25 mg/day) /- dexamethasone
10 mg/day,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 1-21
Primary Comparison MPR-R vs. MP
Placebo
MP M 0.18 mg/kg, days 1-4 P 2 mg/kg, days
1-4 PBO days 1-21
Secondary Comparison MPR-R vs. MPR Addition of
MPR arm per EMEA advice
Placebo
Double-Blind Treatment Phase
Open-Label Extension/Follow-Up Phase
Stratified by age ( 75 vs. gt 75 years) and stage
(ISS 1,2 vs. 3)
M, melphalan P, prednisone R, lenalidomide
PBO, placebo.
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Response PFS MPR-R vs. MP vs. MPR
RR (CR) 77(10) vs.
50(3) vs. 68(3)
Median PFS
MPR-R 31 months
MPR 14 months
MP 13 months
Median follow-up 30 months
Palumbo et al. N Engl J Med 2012 366 1759-69
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OS MPR-R vs. MPR vs. MP
Median follow-up 30 months
Palumbo et al. N Engl J Med 2012 366 1759-69
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AEs During Induction MPR-R vs. MP vs. MPR
MPR-R(N 150) MPR(N 152) MP(N 153)
Hematological, G3 G4 G3 G4 G3 G4
Neutropenia 67 35 64 32 29 8
Thrombocytopenia 35 11 38 14 12 4
Non-hematological,
Infections 9 1 13 2 7 -
DVT 1 - 4 - 1 -
SPM, n 12 9 4
- AML 5 2 -
- MDS 2 3 1
- Non-hematologic SPM 5 4 3
DVT, deep vein thrombosis SMP Second primary
malignancy AML, acute myelogenous leukemia MDS,
myelodysplastic syndrome
Palumbo et al. N Engl J Med 2012 366 1759-69
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BORTEZOMIB
26
VISTA Bortezomib (V) as Initial Standard Therapy
in Multiple Myeloma Assessment with Melphalan
and Prednisone

• Patients Symptomatic multiple myeloma/end organ
  damage with measurable disease
• 65 years or lt 65 years and not
  transplant-eligible KPS 60

VMP Cycles 14 Bortezomib 1.3 mg/m2 IV, d
1,4,8,11,22,25,29,32 Melphalan 9 mg/m2 IV, and
prednisone 60 mg/m2 IV, d 14 Cycles
59 Bortezomib 1.3 mg/m2 IV, d 1,8,22,29 Melphalan
9 mg/m2 IV and prednisone 60 mg/m2 IV, d 14
R A N D O M I Z E

• Primary end point TTP
• Secondary end points CR rate, ORR, time to
  response, DOR, time to next therapy, OS, PFS, QoL
  (PRO)

9 x 6-week cycles (54 weeks) in both arms
MP Cycles 19 Melphalan 9 mg/m2 IV and
prednisone 60 mg/m2 IV, d 14

• Stratification ß2-microglobulin, albumin, region

27
BortezomibMP (VMP) vs. MP Efficacy Data (682
patients)
ORR VMP 71, MP 35,
CR VMP 30, MP 4
San Miguel et al. N Engl J Med 2008359906917
Updated by Mateos et al JCO 2010
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OS (ITT)31 reduced risk of death with VMP
Median OS benefit 13.3 months 5-year OS rates
46.0 vs 34.4
100 90 80 70 60 50 40 30 20 10 0
Patients alive ()
Group N Event Median HR (95 CI) P-value MP 338 21
1 43.1 VMP 344 176 56.4 0.695 (0.567,
0.852) 0.0004
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Time (months)
Number of patients at risk 338 301 262 240 216 1
96 168 153 133 112 61 24 3 344 300 288 270 246 23
2 216 199 176 158 78 34 1
San Miguel et al. ASH 2011 abstract 476
29
Grade 3/4 Adverse Events
VMP (n340) VMP (n340) MP (n337) MP (n337)
Gr 3 Gr 4 Gr 3 Gr 4
Neutropenia, 30 10 23 15
Thrombocytopenia, 20 17 16 14
GI, 19 1 5 lt1
Peripheral Sensory Neuropathy, 13 lt1 0 0
Pneumonia, 5 2 4 1
Herpes Zoster, 3 0 2 0
Hematological SPM, n() 3(1) 3(1) 3(1) 3(1)
Non-hematological SPM, n() 16(5) 16(5) 10(3) 10(3)
San Miguel et al. ASH 2011 abstract
476 1Howlader N, et al. SEER Cancer Statistics
Review, 1975-2008. http//seer.cancer.gov/csr/197
5_2008/browse_csr.php?section2pagesect_02_table
.07.html
30
Progress in the Treatment of Elderly Patients
with MM

• Novel agents SHOULD be included
• Evidence based bortezomib, lenalidomide gt
  thalidomide
• Generating promising data lenalidomide,
  bortezomib, carfilzomib

31
Treatment of Elderly MM Patients Leading Questions

• What is the goal of treatment (does CR matter)?
• What is the best induction treatment?
• Is it possible to individualize the treatment?
• Can novel drugs improve outcome

32
2-Year Mortality Rate for Persons Age 70 Years
and Older

• 8 if fully independent
• 14 if dependent in IADL
• 27 if dependent in ADL
• ?40 if institutionalized

Reuben. Am J Med. 199293663.
33
Comorbidity is a Key Factor in Survival
Age-Comorbidity Score
Actual 10-Year Survival ()
N
0-1 369 97-99
2 136 87
3 109 79
4 42 47
5 29 34
Charlson et al. J Chronic Dis. 198740373.
34
Functional Assessment
35
UPFRONT Protocol
Induction 21-day cycles
Maintenance 35-day cycles
Cycles 14
Cycles 58
Cycles 913
VcDVc 1.3 mg/m2, days 1,4,8,11D 20 mg, days
1,2,4,5,8,9,11,12
Vc 1.3 mg/m2, days 1,4,8,11D 20 mg, days
1,2,4,5
Vc 1.6 mg/m2, days 1,8,15,22 Rest perioddays
2335
VcTDVc 1.3 mg/m2, days 1,4,8,11T 100 mg, days
121 D 20 mg, days 1,2,4,5,8,9,11,12
Vc 1.3 mg/m2, days 1,4,8,11T 100 mg, days 121
D 20 mg, days 1,2,4,5
RANDOMIZE 111
VcMPVc 1.3 mg/m2, days 1,4,8,11M 9 mg/m2,
days 1,2,3,4 of every other cycle P 60 mg/m2,
days 1,2,3,4 of every other cycle
POSTER presentation ASH 2013
36
Patient Demographics andBaseline Disease
Characteristics
VcD(N100) VcTD (N100) VcMP(N100)
Median age, years (range) 73.5 (3991) 73.0 (3888) 72.0 (4286)
75 years, 48 40 34
80 years, 20 17 13
Male, 58 45 57
Race,
White 78 73 72
Black 9 19 17
Other 11 8 10
Not reported 2 0 1
IgG / IgA / Light chain, 59 / 28 / 13 58 / 28 / 14 63 / 21 / 14
KPS 5060 / 7080 / 90100, 9 / 42 / 48 9 / 38 / 53 13 / 47 / 40
ISS stage I / II / III, 15 / 55 / 29 36 / 33 / 31 26 / 43 / 31
Charlson co-morbidity index 0 / 1 / 2, 51 / 25 / 24 55 / 30 / 15 62 / 24 / 14
Serum creatinine gt1.5 x ULN, 16 13 13
Median b2-microglobulin, mg/L 4.5 3.4 3.7
37
PFS (ITT population N502)
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Proportion of patients
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time (Months)
VD 168 144 123 95 79 68 50 34 25 20 17 15 9 7 2
VTD 167 134 117 84 71 59 45 32 23 17 13 12 6
4 2 VMP167 145 125 102 81 69 57 39 32 21 1
6 11 6 3 1
Patients remaining, n

• Median follow up was 13.4 months for the entire
  study population
• Median PFS was 13.8, 18.4, and 17.3 months for
  the VcD, VcTD and VcMP arms, respectively
• None of the pair-wise comparisons are
  statistically significant

38
Patient-reported QoL(mean global health status
score by treatment arm)

• In all three treatment arms, there was a trend
  for decreasing QoL during induction, followed by
  an improvement/stabilization in QoL during
  maintenance
• There was a trend for poorer QoL in the VTD vs.
  VD and VMP arms

UPFRONT QoL poster (Niesvizky et al., ASH 2011,
abstract 1864)
39
Once-weekly Administration of Bortezomib as a
Strategy to Improve Tolerability
Study details Grade ¾ GI toxicity Grade 3/4 peripheral neuropathy Discontinuation due to AE
VISTA VMP1-3 Bortezomib twice-weekly 20 14 34
(GIMEMA)4 Bortezomib once-weekly - 5 17
(PETHEMA/GEM)5 Bortezomib once-weekly 7 7 12
Discontinuations due to SAEs
1. San Miguel et al. NEJM 2008359906 2. San
Miguel et al. NEJM 2008359906 Supplementary
Appendix 3. Mateos et al. J Clin Oncol
2010282259-66
4. Palumbo et al. JCO 2010 285101-09 5. Mateos
et al. Lancet Oncol 201011934-41
40
Once-weekly Administration of Bortezomib as a
Strategy to Maintain/Improve the Ffficacy
Study details CRPR CR PFS 3 yrs-OS
VISTA VMP1-3 Bortezomib twice-weekly 71 30 TTP24 m 68
Modified VISTA4 (GIMEMA) Bortezomib once-weekly VMPT?VT VMP 90 81 42 24 37 m 27 m 85 80
Modified VISTA5 (PETHEMA) Bortezomib once-weekly VMP vs VTP?VT vs VP 80 23?42 31 m 70
1. San Miguel et al. NEJM 2008359906 2. San
Miguel et al. NEJM 2008359906 Supplementary
Appendix 3. Mateos et al. J Clin Oncol
2010282259-66
4. Palumbo et al. J Clin Oncol 2010285101-9 5.
Mateos et al. Lancet Oncol 201011934-41
41
Once-weekly Administration of Bortezomib as a
Strategy to Improve Tolerability
Study details Planned bortezomib dose Delivered bortezomib dose
VISTA VMP1 Bortezomib twice-weekly 67.6 mg/m2 38.5 mg/m2
Modified VISTA2 Bortezomib once-weekly (GIMEMA) 46.8 mg/m2 39.4 mg/m2
Modified VISTA3 Bortezomib once-weekly (PETHEMA/GEM) 36.4 mg/m2 32.9 mg/m2
Mateos et al. IMW 2011 abstract 175
42
Bortezomib IV versus SC

• 222 relapsed and/or refractory MM patients. Bz is
  given at conventional dose and scheme

Bortezomib IV (n73) Bortezomib SC (n145)
Primary endpoint response after 4/8cycles (single agent bortezomib or /-dex)) Primary endpoint response after 4/8cycles (single agent bortezomib or /-dex)) Primary endpoint response after 4/8cycles (single agent bortezomib or /-dex))
ORR 42/52 42/52
CR 8/12 6/10
TTP 94 m 104 m
Bortezomib IV Bortezomib IV Bortezomib SC Bortezomib SC
All grades Grade 3 All grades Grade 3
Periph Neurop 53 16 38 6
P004 and 003
Moreau et al. Lancet Oncology 2011 12(5)
431-40 Arnulf B et al. Haematologica 2012 Epub
ahead of print
No diferences in pharmakokinetics studies
43
Treatment of Elderly MM Patients Leading Questions

• What is the goal of treatment (does CR matter)?
• What is the best induction treatment?
• Is it possible to individualize the treatment?
• Can novel drugs improve outcome

44

• A phase 1/2 study of carfilzomib in combination
  with lenalidomide and low-dose dexamethasone as a
  frontline treatment for multiple myeloma
• Jakubowiak, et al Blood, 2013

CR 42 gtVGPR 62
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ECOG 00602641
Palumbo 0109319 Fun Neo San
Celgene 0109319
SWOG 0109319
Baz 617591
OncoTx 317811
UPFRONT 507416
Evolution 507442
Boccadoro 1063179
53
Collaborators
Myelomacenter.org
Tomer Mark MD Morton Coleman, MD Roger Pearse, MD Adriana Rossi, MD David Jayabalan Karen Pekle Arthur Perry Susan Matthew, PhD Scott Ely, MD/MPH Selina Chen-Kiang, PhD Monica Guzman, PhD Linda Tangenstam Kathleen Pogonowski Yasphal Agrawal, PhD Paul Christos Stanley Goldsmith MD Maureen Lane PhD Paul Christos