Declining multiple myeloma mortality
rates in the United States following the
introduction of novel therapies
Libby E, Ebaid A, Quintana D, Wiggins C
University of New Mexico Cancer Center
Albuquerque, New Mexico USA
Disclosures
· Employment or leadership position: none
· Consultant or advisory role: none
· Stock ownership: none
· Honoraria: none
· Research funding: none
· Testimony: none
· Other renumeration: none
1
Background
· 1969 Alexanian1 reported the first chemotherapy
regimen to improve survival in patients with
multiple myeloma ( 6 month OS improvement)
· 198090s introduction of autologous stem cell
transplantation was 2nd major milestone in
improved survival2,3 (1 1.5 years gained in OS )
· 2000 arrival of novel agents (thalidomide,
bortezomib and lenalidomide) ushered in further
improvements in OS4 (50% improvement in OS
(44.8 vs 29.9 months; P < .001)
1.
Alexanian et al. JAMA 1969;208:168085.
2.
McElwain TJ,et al. Lancet. 1983;2:822824
3.
Attal,M. N Engl J Med. 1996;335:9197
4.
Kumar et al. Blood. 2008:111: 25162520.
Background
· 1969 Alexanian reported the first
chemotherapy regimen to improve
survival in patients with multiple
myeloma
· 1980s the introduction of autologous
PATIENTS
stem cell transplantation was 2nd major
< 65
milestone in improved survival
· 2000 arrival of novel agents
(thalidomide, bortezomib and
lenalidomide) ushered in further
improvements in OS
2
Major milestones in therapeutic options for myeloma
Milestone
Notes
1962
MelphalanPrednisone
Introduction melphalan in 1960s was
associated with improved survival
1996
Autologous SCT
Several randomized trials demonstrated
survival advantage for SCT compared to
conventional chemotherapy
1999
Thalidomide
Improved response and PFS compared to
dexamethasone. When added to MP, it
improves OS compared to MP alone
2003
Bortezomib
improved survival compared to highdose
dexamethasone in relapsed MM
2003
Tandem autotransplant
Tandem SCT improved OS compared with
single transplantation (in
pts failing to achieve a VGPR to first SCT)
2005
Lenalidomide
Lenalidomide and dexamethasone
improve OS compared with
dexamethasone in relapsed myeloma
Background
· Data on improvements in survival for MM
based on results of randomized studies
· OS benefit for patients 65 convincing 14
· OS benefit for elderly patients is uncertain
· Average age of newly diagnosed patients
with myeloma is 70
1.
Brenner etal . Blood. 2008;111:25212526
2.
Turesson et al J Clin Oncol . 2009 28:830834
3.
Kastritis 2009 Leukemia 23, 11521157.
4.
Kumar et al. Blood. 2008:111: 25162520
3
Background
· Use caution when comparing randomized trial results
· Spectrum of patients may not represent general
population
· Older patients and those with poor performance
status often excluded
· Patients treated in referral centers and those
included in clinical trials often represent a selected
patient population
· Many trials comprise only a minority of all patients in
the recruitment area limiting the generalizability
Background
· Success reported in clinical research trials may
not translate to impact on the MM general
population
· There are a handful of results that indicate the
introduction of novel agents is increasing the OS
of MM patients treated outside the context of
clinical trials
· We studied a national database of unselected
patients to analyze the impact of the novel agents
on mortality and survival rates for MM patients of
all ages
4
Mention other presentations that
looked at survival at this meeting
Methods
· Death records from the US National Center for
Health Statistics (CDC) were used to
characterize time trends in MM mortality
rates in the United States during the period
19692007
· Represents all mortality data for all 50 states
· Temporal trends in MM mortality rates were
characterized with joinpoint regression
techniques
5
Methods
· Search criteria: 1) deaths due to myeloma;
2) Deaths occuring during calender years
19692008 (inclusive); 3) deaths occuring
among residents of the US
· Based on death certificate data
· Mortality and survival analysis was
performed separately for two age cohorts
(< 65 years of age and 65) based on the
age limit used for application of HDT-SCT
Joinpoint Regression Program
· Statistical software for analysis of trends where several
different lines are connected together at the "joinpoints"
· Cancer trends reported in NCI publications are calculated
using the Joinpoint Regression Program to analyze rates
calculated by SEER Stat software
· SEER*Stat provides cancer researchers with a mechanism
for viewing data fields in individual cancer records and
producing statistics useful in studying the impact of
cancer on a population
· Joinpoint software takes trend data (e.g. cancer rates)
and fits the simplest model that the data allow
6
RESULTS 19692007
NUMBER OF MYELOMA DEATHS
STUDIED
AGE < 65
64,161
AGE 65
198,175
TOTAL
262,336
Results
· In the US population under 65 years of age, MM
mortality increased from 19691995 (Annual
Percent Change (APC) = +0.5% ; p < 0.01) and
decreased rapidly thereafter (APC= 2.35 %;
p< 0.01)
· Among those 65 years of age and older, increasing
MM mortality rates from 196993 were followed
by a plateau during the period 19932002
· Rates among the elderly declined after 2002
(APC = 1.77%; p < 0.01)
7
Myeloma Mortality: <65 Years of Age
Agespecific mortality rates per 100,000
19692007
1.20
1.00
0.80
100,000 0.60
pere 0.40
Rat
0.20
0.00
69
71
73
75
77
79
81
83
85
87
89
91
93
95
97
99
01
03
05
07
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
20
20
20
20
Year of Death
Myeloma Mortality: 65 years of age
Agespecific mortality rates per 100,000
19692007
25.00
20.00
15.00
100,000
per 10.00
e
Rat
5.00
0.00
69
71
73
75
77
79
81
83
85
87
89
91
93
95
97
99
01
03
05
07
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
20
20
20
20
Year of Death
8
Joinpoint Analysis
<65 years of age
Joinpoint Analysis
65 years of age
9
Myeloma Mortality: <65 Years of Age
Agespecific mortality rates per 100,000
United States All Races, 19692007
1.40
1.20
1.00
0.80
100,000
0.60
pere
19691995 Annual Percent Change 0.50 (p<0.01)
Rat 0.40
19952007 Annual Percent Change 2.35 (p<0.01)
0.20
0.00
69
71
73
75
77
79
81
83
85
87
89
91
93
95
97
99
01
03
05
07
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
20
20
20
20
Year of Death
Myeloma Mortality: 65+ Years of Age
Agespecific mortality rates per 100,000
United States All Races, 19692007
30.00
25.00
20.00
100,000 15.00
pere
19691978 Annual Percent Change +3.23% (p<0.01)
10.00
Rat
19781993 Annual Percent Change +1.78% (p<0.01)
19932002 Annual Percent Change 0.16% (p=0.37)
5.00
20022007 Annual Percent Change 1.77 % (p<0.01)
0.00
69
71
73
75
77
79
81
83
85
87
89
91
93
95
97
99
01
03
05
07
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
20
20
20
20
Year of Death
10
· Queried SEER for survival rates of MM patients 1980
2007
· SEER collects and publishes cancer incidence and
survival data from populationbased cancer registries
covering 28 %of US population
· Data included in SEER database are from population
based cancer registries in Connecticut, New Mexico,
Utah, Iowa, Hawaii, Atlanta, Detroit, SeattlePuget
Sound, and San FranciscoOakland that together cover
a population of >30 million people
21
Myeloma Survival: All Ages
SEER Program, 19802007
SUBJECTS:
Newly diagnosed (incident) cases of
Myeloma diagnosed in 9 core areas
of the SEER Program during the time
period 19802007
NUMBER OF SUBJECTS:
Diagnosed 198089: 7901
(48.82 % alive after 3 years)
Diagnosed 199099: 9353
(50.56 % alive after 3 years)
Diagnosed 20002007: 8300
(57.64% alive after 3 years)
Total subjects = 25,554
PValue: <0.0001
22
11
Myeloma Survival: < 66 Years of Age at Diagnosis
SEER Program, 19802007
SUBJECTS:
Newly diagnosed (incident) cases of
Myeloma diagnosed in 9 core areas
of the SEER Program during the time
period 19802007
NUMBER OF SUBJECTS:
Diagnosed 198089: 3124
(55.66% alive after 3 years)
Diagnosed 199099: 3550
(59.97% alive after 3 years)
Diagnosed 20002007: 3623
(68.15% alive after 3 years)
PValue: <0.0001
Total = 10,297 patients
23
Myeloma Survival: 66+ Years of Age at Diagnosis
SEER Program, 19802007
SUBJECTS:
Newly diagnosed (incident)
cases of Myeloma diagnosed in
9 core areas of the SEER
Program during the time period
19802007
NUMBER OF SUBJECTS:
Diagnosed 198089: 4777
(44.01% alive after 3 years)
Diagnosed 199099: 5803
(44.89 % alive after 3 years)
Diagnosed 20002007: 4677
(49.03 % alive after 3 years)
PValue: 0.005
Total # patients = 15,257
24
12
Strengths /Weaknesses
· Analysis of long time period
· Large sample size (s)
· Unselected patients
· Death certificate data
· Variables such as supportive care could have
contributed to improved survival
· Changes in survival can be influenced by changes
in diagnostic practice and access to health care,
causing earlier detection of the disease
· Lack of treatment information
Conclusion(s)
· Results confirm earlier reports showing improvement
in the outcome of younger myeloma patients
· Declining MM mortality rates in young patients were
observed during a time period after bone marrow
transplantation became the preferred therapy for
patients in this age group
· Similarly, declining MM mortality rates for elderly
patients were observed shortly after thalidomide was
licensed by the FDA for treatment of this disease in
2001
· Conclusion: the novel agents are contributing to
improved survival for myeloma patients of all ages
13