treatment of transplant ineligible/elderly mm patients
DESCRIPTION
Treatment of Transplant Ineligible/Elderly MM Patients. Ruben Niesvizky Department of Medicine, Division of Hematology/Oncology, Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA. Myelomacenter.org [email protected]. Disclosures. - PowerPoint PPT PresentationTRANSCRIPT
Treatment of Transplant Ineligible/Elderly MM Patients
Ruben Niesvizky Department of Medicine, Division of Hematology/Oncology,
Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA
Disclosures
•Speaker’s bureau: Celgene, Millennium, Onyx
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
• β2M: 15.0
• BM: 50% plasma cells
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:
1. 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
2. Patients over the age of 65 should not be considered for aggressive therapies
• 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%
The Elderly Patient
The median age at diagnosis is 70 years
.
Eld
erly
Old
er
37%
28%
35%
Palumbo A, et al. Hematology Am Soc Hematol Educ Program. 2009:566-577.; 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
< 65 years >65 years
Myeloma: 5-year Relative Survival Rates
42.9% 25.2 %
SEER 1995-2001
Novel Agent Limitations in the Aging Population
Median OS<65 60 m
Median OS>65 32 m
Kumar et al. Blood 2007
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
Treatment of Elderly MM PatientsLeading Questions
Treatment of Elderly MM PatientsLeading Questions
Treatment of Elderly MM PatientsLeading Questions
Treatment of Elderly MM PatientsLeading Questions
Median not available, OS calculated from 2yr (San Miguel), 3yr (Palumbo) and 5yr (Zervas) estimates
Keldsen 1993
Hulin 2007
Facon 2006
Facon 2007
Palumbo 2006
Osterborg 1993
Oken 1999
San Miguel 2007
Zervas 2001
Hernandez 2004
Ludwig 2007
Joshua 1997
Waage 2007
MEAN
-20 -15 -10 -5 0 5 10 15 20 25 30 35 40
Percent Improvement in Survival
• 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
Mean = 3.6%
ΔCR/nCR OS ΔOS
+10% 35m +12.6m
+10% 50m +18m
• 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
CR in Non-Transplant Settingvan de Velde et al. Haematologica 2007
Hematologic CR Correlates with Long-term PFS and OS in Elderly Patients Treated with Novel Agents
Gay et al. Blood 2011; 117(11):3025-31
PFS OS
P<0.001 P<0.001
CR
VGPR
PR
CR
VGPR
PR
Pro
bab
ility
Pro
bab
ility
• Retrospective analysis: 3 randomized European trials of GIMEMA and HOVON groups (N=1175)
• First-line treatment
MP (n=332), MPT (n=332), VMP (n=257), VMPT-VT (n=254)
•Significant benefit also seen when analysis is restricted to patients >75 years old
6050403020100
100
80
60
40
20
0
Months
P =0.001
PFS
Immunophenotypic CR 90% at 3y
“Stringent CR” 38% at 3y
Conventional CR 57% at 3y
PR (≥70% reduction) 28% at 3y
Paiva et al; J Clin Oncol. 2011;29(12):1627-33.
The Better the Quality of the Response the Longer the Survival (Immunophenotypic CR): GEM2005>65y
PFS
Sequential Approach NDMM Patients
PAD, bortezomib-pegylated doxorubicin-dexamethasone; 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
TransplantMEL100two courses
Median follow-up 66 months Median age 70 years
OS according response
monthsmonths monthsmonths monthsmonths
InductionPAD
four 21-day courses
ConsolidationLen-Pdn
four 28-day courses
MaintenanceLen
until progression
0.00
0.25
0.50
0.75
1.00
20 40 60 80 100
CRCR
VGPRVGPR
PRPR
12
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70 80
Median 47 moMedian 47 mo
Gay F, et al. Gr. Emat. Milan 19 November 2012Gay F, et al. Gr. Emat. Milan 19 November 2012
CR
PR
P<0.0010.00
0.25
0.50
0.75
1.00
10 20 30 40 50 60
PFS according response
VGPRVGPR
Important Aim of Treatment: Achievement of high-quality, sustained CR
balanced with acceptable toxicity
CR Should Be an Important Objective in Elderly MM Patients
Treatment of Elderly MM PatientsLeading Questions
Treatment of Elderly MM PatientsLeading Questions
THALIDOMIDE
MPT vs. MP : Efficacy in Newly Diagnosed Elderly Myeloma Patients
3 trials (IFM991, IFM012, HOVON3)………. > RR, PFS & OS 2 trial (GIMEMA4, TURKISH5)………………. > RR, PFS 1 trial (Nordic6 )…………………………….. > RR
RR : 59% vs. 37 % (>22%)
CR : 10% vs. 2,5% (>8 %)
PFS : 20,4 vs. 15 m ( 6 m)………… HR 0,67
OS : 39,3 vs. 32,7 m (>6 m)…………HR 0,83
• Thal maintenance in Italian, Nordic, Hovon
1.Facon et al. Lancet 2007;370:1209–1218; 2. Hulin et al. JCO 2009; 27(22):3664-70 ; 3. Wijermans JCO 2010; 28: 3160-6; 4. Palumbo et al. Blood 2008; 112:
3107–3114; 5. Beksac M et al. Eur J Haematol 2010; 86:16-22; 6. Waage et al Blood 2010;116(9):1405-12; Fayers PM et al. Blood 2011; 118(5): 1239-47
MPT vs. MP : Toxicity
Palumbo A. Haematologica 2012; Epub ahead on August 8Palumbo A. Haematologica 2012; Epub ahead on August 8
*Appropriate thromboprophylaxis is required** p of significant value
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%
Other Thalidomide-based Combinations in Front-line
Study Results Reference
Phase 3
Thal/dex vs MP
• In patients > 75 years, OS longer with MP (41 vs 20m)• In patients <75 years, similar OS • Higher mortality during 1st y with thal/dex vs MP (28 vs 16, p=0.02)
Ludwig et al. Blood,2009 ;113:3435-43
Phase 3
CTDa vs MP
Morgan et al. Blood 2011; 118(5): 1231-8
CTDa MP
≥ PR 64% 33%
CR 13% 3%
OS 33m 31m
Thal/
Dex*MP
≥ PR 73% 42%
TTP 21m 29m
OS 41m 49m
Thal: 200 mg daily; Dex: 40 mg days 1-4; 9-12
LENALIDOMIDE
Secondary Comparison MPR-R vs. MPRAddition of MPR arm per EMEA advice
MPM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4PBO: days 1-21
Primary Comparison MPR-R vs. MP
MPRM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day po, days 1-21
Placebo
Placebo
Lenalidomide(R) +/- MP: MPR-R vs. MPR vs. MP
Phase III Study Scheme N=459 patients > 65years
M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo.
MPR-RM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day po, days 1-21
RA
ND
OM
ISA
TIO
N
Double-Blind Treatment Phase
Diseaseprogression
LenalidomideContinued Tx
Lenalidomide (25 mg/day) +/- dexamethasone
Open-Label Extension/Follow-Up Phase
Stratified by age (≤ 75 vs. > 75 years) and stage (ISS 1,2 vs. 3)
10 mg/day,days 1-21
Cycles (28-day) 1-9 Cycles 10+
Response & PFS: MPR-R vs. MP vs. MPR
%RR (%CR): 77(10) vs. 50(3) vs. 68(3)
Palumbo et al. N Engl J Med 2012; 366: 1759-69Palumbo et al. N Engl J Med 2012; 366: 1759-69
Median PFS
MPR-R 31 months
MPR 14 months
MP 13 months
Median follow-up 30 months
HR 0.49 P < .0000001
Time (months)0 5 10 15 20 25 30 35 40
0
25
50
75
100
HR 0.40P = .153
OS: MPR-R vs. MPR vs. MP
Median follow-up 30 months
Palumbo et al. N Engl J Med 2012; 366: 1759-69Palumbo et al. N Engl J Med 2012; 366: 1759-69
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 3DVT, deep vein thrombosis; SMP: Second primary malignancy; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome
AEs During Induction: MPR-R vs. MP vs. MPR
Palumbo et al. N Engl J Med 2012; 366: 1759-69Palumbo et al. N Engl J Med 2012; 366: 1759-69
BORTEZOMIB
VMPCycles 1–4Bortezomib 1.3 mg/m2 IV, d 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 IV, and prednisone 60 mg/m2 IV, d 1–4
Cycles 5–9Bortezomib 1.3 mg/m2 IV, d 1,8,22,29Melphalan 9 mg/m2 IV and prednisone 60 mg/m2 IV, d 1–4
MPCycles 1–9 Melphalan 9 mg/m2 IV and prednisone 60 mg/m2 IV, d 1–4
RANDOMIZE
9 x 6-week cycles (54 weeks) in both arms
• Stratification: β2-microglobulin, albumin, region
Primary end point: TTPSecondary end points:
CR rate, ORR, time to response, DOR, time to next therapy, OS, PFS, QoL (PRO)
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 < 65 years and not transplant-eligible; KPS ≥ 60%
Bortezomib+MP (VMP) vs. MP: Efficacy Data (682 patients)
San Miguel et al. N Engl J Med 2008;359:906–917; Updated by Mateos et al JCO 2010
ORR: VMP 71%, MP 35%, CR: VMP 30%, MP 4%
0 3 6 9 12
Time (months)
15 18 21 24 27
0
20
40
60
80
100
VMPMP
Pat
ient
s w
ithou
t ev
ent
(%)
Time (months)0 4 8 12 16 20 24 28 32 36 40
0
20
40
60
80
100VMPMP
Pat
ient
s w
ithou
t ev
ent
(%)
Time to progression Overall survival
52% reduced risk of progression on VMP ~36% reduced risk of death on VMP
Median follow-up 36.7 months3-year OS: VMP: 69% MP: 54%, P=0.0008
VMP: 24.0 monthsMP: 16.6 months, P<0.000001
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
Pat
ient
s al
ive
(%)
0 6 12 18 24 30 36 42 48 54 60 66 72 78Time (months)
Number of patients at risk:338 301 262 240 216 196 168 153 133 112 61 24 3344 300 288 270 246 232 216 199 176 158 78 34 1
Group N Event Median HR (95% CI) P-value
MP 338 211 43.1
VMP 344 176 56.4 0.695 (0.567, 0.852) 0.0004
San Miguel et al. ASH 2011; abstract 476
Grade 3/4 Adverse Events
VMP (n=340) MP (n=337)Gr 3 Gr 4 Gr 3 Gr
4 Neutropenia, % 30 10 23 15
Thrombocytopenia, % 20 17 16 14
GI, % 19 1 5 <1
Peripheral Sensory Neuropathy, % 13 <1 0 0
Pneumonia, % 5 2 4 1
Herpes Zoster, % 3 0 2 0
Hematological SPM*, n(%) 3(1%) 3(1%)
Non-hematological SPM*, n(%) 16(5%) 10(3%)
San Miguel et al. ASH 2011; abstract 4761Howlader N, et al. SEER Cancer Statistics Review, 1975-2008.
http://seer.cancer.gov/csr/1975_2008/browse_csr.php?section=2&page=sect_02_table.07.html
Progress in the Treatment of Elderly Patients with MM
•Novel agents SHOULD be included: •Evidence based: bortezomib, lenalidomide > thalidomide•Generating promising data: lenalidomide, bortezomib, carfilzomib
Treatment of Elderly MM PatientsLeading Questions
Treatment of Elderly MM PatientsLeading Questions
• 8% if fully independent
• 14% if dependent in IADL
• 27% if dependent in ADL
• 40% if institutionalized
2-Year Mortality Rate for Persons Age 70 Years and Older
Reuben. Am J Med. 1992;93:663.
Comorbidity is a Key Factor in Survival
Charlson et al. J Chronic Dis. 1987;40:373.
Age-Comorbidity Score N
Actual 10-Year Survival (%)
0-1 369 97-99
2 136 87
3 109 79
4 42 47
5 29 34
Functional Assessment
UPFRONT Protocol
Induction: 21-day cyclesMaintenance: 35-day cycles
Cycles 1–4 Cycles 5–8
Vc: 1.6 mg/m2, days 1,8,15,22Rest period:days 23–35
VcDVc: 1.3 mg/m2, days 1,4,8,11D: 20 mg, days 1,2,4,5,8,9,11,12
VcTDVc: 1.3 mg/m2, days 1,4,8,11T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5,8,9,11,12
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 cycleR
AN
DO
MIZ
E 1
:1:1
Vc: 1.3 mg/m2, days 1,4,8,11D: 20 mg, days 1,2,4,5
Vc: 1.3 mg/m2, days 1,4,8,11T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5
Cycles 9–13
POSTER presentation ASH: 2013
VcD(N=100)
VcTD (N=100)
VcMP(N=100)
Median age, years (range) 73.5 (39–91) 73.0 (38–88) 72.0 (42–86)
≥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 50–60 / 70–80 / 90–100, % 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 / 14Serum creatinine >1.5 x ULN, % 16 13 13
Median2-microglobulin, mg/L 4.5 3.4 3.7
Patient Demographics andBaseline Disease Characteristics
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
PFS (ITT population N=502)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
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 – –VMP:167 145 125 102 81 69 57 39 32 21 16 11 6 3 1 – – –
Time (Months)
Pro
po
rtio
n o
f p
atie
nts VcTD (N=168, 29% PFS events)
VcD (N=167, 40% PFS events)
VcMP (N=167, 36% PFS events)
Pat
ient
s re
mai
ning
, n
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 armsUPFRONT QoL poster (Niesvizky et al., ASH 2011, abstract 1864)
58
56
54
52
50
48
46
44
42
40
Sco
re
Baseline Cycle 3 Day 1
Cycle 5 Day 1
Cycle 7 Day 1
Cycle 9 Day 1
Cycle 11 Day 1
Cycle 13 Day 1
Timepoint
VD VTD VMP
Induction Maintenance
Once-weekly Administration of Bortezomib as a Strategy to Improve Tolerability
Study detailsGrade ¾
GI toxicityGrade 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 2008;359:9062. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix3. Mateos et al. J Clin Oncol 2010;28:2259-66
4. Palumbo et al. JCO 2010; 28:5101-095. Mateos et al. Lancet Oncol 2010;11:934-41
Study details CR+PR CR PFS 3 yrs-OS
VISTA: VMP1-3
Bortezomib twice-weekly 71% 30% TTP:24 m 68%
Modified VISTA4 (GIMEMA)Bortezomib once-weeklyVMPTVTVMP
90%81%
42%24%
37 m27 m
85%80%
Modified VISTA5 (PETHEMA)Bortezomib once-weeklyVMP vs VTPVT vs VP
80%23%42% 31 m 70%
Once-weekly Administration of Bortezomib as a Strategy to Maintain/Improve the Ffficacy
1. San Miguel et al. NEJM 2008;359:9062. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix3. Mateos et al. J Clin Oncol 2010;28:2259-66
4. Palumbo et al. J Clin Oncol 2010;28:5101-95. Mateos et al. Lancet Oncol 2010;11:934-41
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
Bortezomib IV versus SC222 relapsed and/or refractory MM patients. Bz is given at conventional dose and scheme
Moreau et al. Lancet Oncology 2011; 12(5): 431-40Arnulf B et al. Haematologica 2012: Epub ahead of print
Bortezomib IV (n=73) Bortezomib SC (n=145)
Primary endpoint: response after 4/8cycles (single agent bortezomib or +/-dex))
ORR 42%/52% 42%/52%
CR 8%/12% 6%/10%
TTP 9·4 m 10·4 m
Bortezomib IV Bortezomib SC
All grades Grade ≥3 All grades Grade ≥3
Periph Neurop 53% 16% 38% 6%P=0·04 and 0·03
No diferences in pharmakokinetics studies
Treatment of Elderly MM PatientsLeading Questions
Treatment of Elderly MM PatientsLeading Questions
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%>VGPR 62%
ECOG 00602641
ECOG 00602641
Palumbo0109319
Fun Neo San
Palumbo0109319
Fun Neo San
Celgene0109319Celgene0109319
SWOG0109319
SWOG0109319
Baz 617591 Baz 617591
OncoTx317811
OncoTx317811
UPFRONT507416
UPFRONT507416
Evolution507442
Evolution507442
Boccadoro1063179
Boccadoro1063179
Collaborators
Tomer Mark MDMorton Coleman, MDRoger Pearse, MDAdriana Rossi, MDDavid JayabalanKaren PekleArthur PerrySusan Matthew, PhD Scott Ely, MD/MPHSelina Chen-Kiang, PhDMonica Guzman, PhD
Linda TangenstamKathleen PogonowskiYasphal Agrawal, PhDPaul Christos
Stanley Goldsmith MD
Maureen Lane PhD
Paul Christos
Myelomacenter.org