From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on May 14, 2008. For personal use
only.
2008 111: 4039-4047
Prepublished online Feb 11, 2008;
doi:10.1182/blood-2007-03-081018
Myeloma in patients younger than age 50 years presents with more
favorable features and shows better survival: an analysis of 10 549
patients from the International Myeloma Working Group
Heinz Ludwig, Brian G. M. Durie, Vanessa Bolejack, Ingemar Turesson, Robert A. Kyle, Joan Blade,
Rafael Fonseca, Meletios Dimopoulos, Kazuyuki Shimizu, Jesus San Miguel, Jan Westin, Jean-Luc
Harousseau, Meral Beksac, Mario Boccadoro, Antonio Palumbo, Bart Barlogie, Chaim Shustik,
Michele Cavo, Philip R. Greipp, Douglas Joshua, Michel Attal, Pieter Sonneveld and John Crowley
Updated information and services can be found at:
http://bloodjournal.hematologylibrary.org/cgi/content/full/111/8/4039
Articles on similar topics may be found in the following Blood collections:
Clinical Trials and Observations (2356 articles)
Neoplasia (3993 articles)
Information about reproducing this article in parts or in its entirety may be found online at:
http://bloodjournal.hematologylibrary.org/misc/rights.dtl#repub_requests
Information about ordering reprints may be found online at:
http://bloodjournal.hematologylibrary.org/misc/rights.dtl#reprints
Information about subscriptions and ASH membership may be found online at:
http://bloodjournal.hematologylibrary.org/subscriptions/index.dtl
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published
semimonthly by the American Society of Hematology, 1900 M St, NW, Suite
200, Washington DC 20036.
Copyright 2007 by The American Society of Hematology; all rights
.
reserved

---

From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on May 14, 2008. For personal use
only.
CLINICAL TRIALS AND OBSERVATIONS
Myeloma in patients younger than age 50 years presents with more favorable
features and shows better survival: an analysis of 10 549 patients from the
International Myeloma Working Group
Heinz Ludwig,1 Brian G. M. Durie,2 Vanessa Bolejack,3 Ingemar Turesson,4 Robert A. Kyle,5 Joan Blade,6 Rafael Fonseca,7
Meletios Dimopoulos,8 Kazuyuki Shimizu,9 Jesus San Miguel,10 Jan Westin,11 Jean-Luc Harousseau,12 Meral Beksac,13
Mario Boccadoro,14 Antonio Palumbo,14 Bart Barlogie,15 Chaim Shustik,16 Michele Cavo,17 Philip R. Greipp,5
Douglas Joshua,18 Michel Attal,19 Pieter Sonneveld,20 and John Crowley3
1Department of Medicine, Wilhelminenspital, Vienna, Austria; 2Southwest Oncology Group, International Myeloma Foundation and Cedars Sinai Comprehensive
Cancer Center, Los Angeles, CA; 3Cancer Research and Biostatistics, Seattle, WA; 4Department of Hematology, University Hospital, Malmo¨, Sweden; 5Division
of Hematology, Mayo Clinic, Rochester, MN; 6Hematology Department, Institute of Hematology and Oncology, Hospital Clinic, Institut d' Investigacious
Biomediques August Pi i Sunyer, Barcelona, Spain; 7Division of Hematology and Oncology, Mayo Clinic Comprehensive Cancer Center, Scottsdale, AZ;
8Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; 9Department of Medicine, Nagoya City Midori General Hospital,
Nagoya, Japan; 10University Hospital of Salamanca, Salamanca, Spain; 11Department of Hematology, University Hospital, Lund, Sweden; 12Division of
Hematology, Centre Hospitalier Universitaire Hotel-Dieu, Nantes, France; 13Department of Microbiology and Clinical Microbiology, Ankara University School of
Medicine, Ibn-i Sina Hospital, Ankara, Turkey; 14Divisione Universitaria di Ematologia, Ospedale Molinette, Torino, Italy; 15Myeloma Institute for Research and
Therapy, University of Arkansas for Medical Sciences, Little Rock, AR; 16Department of Medicine, McGill University, Montreal, QC; 17Institute of Hematology and
Medical Oncology Seragnoli, University of Bologna, Bologna, Italy; 18Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales,
Australia; 19Service d'He´matologie, Ho^pital Purpan, Toulouse, France; and 20Department of Hematology, Erasmus MC, Rotterdam, The Netherlands
We analyzed the presenting features and
performance status. Survival was signifi-
independent risk factors identified for
survival in 1689 patients with multiple
cantly longer in young patients (median,
conventional therapy were also relevant
myeloma aged younger than 50 years
5.2 years vs 3.7 years; P < .001) both
for autologous transplantation. After ad-
compared with 8860 patients 50 years of
after conventional (median, 4.5 years vs
justing for normal mortality, lower ISS
age and older. Of the total 10 549 patients,
3.3 years; P < .001) or high-dose therapy
stage and other favorable prognostic fea-
7765 received conventional therapy and
(median, 7.5 years vs 5.7 years; P
.04).
tures seem to account for the signifi-
2784 received high-dose therapy. Young
The 10-year survival rate was 19% after
cantly longer survival of young patients
patients were more frequently male, had
conventional therapy and 43% after high-
with multiple myeloma with age remain-
more favorable features such as low Inter-
dose therapy in young patients, and 8%
ing a risk factor during conventional
national Staging System (ISS) and Durie-
and 29%, respectively, in older patients.
therapy. (Blood. 2008;111:4039-4047)
Salmon stage as well as less frequently
Multivariate analysis revealed age as an
adverse prognostic factors including high
independent risk factor during conven-
C-reactive protein (CRP), low hemoglo-
tional therapy, but not after autologous
bin, increased serum creatinine, and poor
transplantation. A total of 5 of the 10
© 2008 by The American Society of Hematology
Introduction
Multiple myeloma is uncommon in young persons. The inci-
hypercalcemia (29%) at presentation and median survival of
dence increases steadily with increasing age to a peak age-
54 months in 72 patients younger than 40 years.4 The question
specific incidence of more than 40 per 100 000 in persons older
regarding differences in presentation and in outcome in different age
than 80 years.1,2 Whether the presentation and prognosis of
groups is clinically relevant since significant differences in prognostic
multiple myeloma in young patients differs from the disease
and biologic features have been demonstrated in several other malignan-
usually encountered in the typical elderly patient has only rarely
cies. Prognosis is significantly better in young patients with acute
been addressed and never in a large patient cohort. A previous
myeloid leukemia who have less frequently adverse cytogenetic abnor-
study in 61 patients aged younger than 50 years showed no
malities,5 but significantly worse in young patients with breast cancer
difference in presenting features compared with older patients.3
whose tumors are less frequently hormone responsive.6
Survival was significantly better compared with the older patient
Here, we report the presenting features and outcome after
cohort but was significantly shorter in young patients after findings
conventional and high-dose therapy in 10 549 patients with my-
were corrected for differences in life expectancy.3 Blade et al
eloma and compare the findings obtained in 1689 patients younger
reported an increased frequency of renal impairment (30%) and
than 50 years of age with those of 8860 older patients.
Submitted March 21, 2007; accepted January 14, 2008. Prepublished online as
The publication costs of this article were defrayed in part by page charge
Blood First Edition paper, February 11, 2008; DOI 10.1182/blood-2007-
payment. Therefore, and solely to indicate this fact, this article is hereby
03-081018.
marked ``advertisement'' in accordance with 18 USC section 1734.
The online version of this article contains a data supplement.
© 2008 by The American Society of Hematology
BLOOD, 15 APRIL 2008 VOLUME 111, NUMBER 8
4039

---

From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on May 14, 2008. For personal use
only.
4040
LUDWIG et al
BLOOD, 15 APRIL 2008 VOLUME 111, NUMBER 8
age. Only 312 patients were younger than 40 years, and 27 patients
Methods
were younger than 30 years. Median age of the 8860 patients
50 years or older was 62 years (range, 50-93 years), and the median
A total of 17 institutions and/or study groups from North America, Europe,
age of the 1689 patients less than age 50 years was 36 years (range,
and Japan participated in this study. A total of 1006 patients were entered
20-49 years).
from the Japanese myeloma study group, 6457 from European centers
The presenting features of patients younger than 50 years of age
(Austria, Spain, France, Italy, Nordic countries, Turkey, and the United
versus 50 years and older are shown in Table 1. The younger
Kingdom), and 2386 from North America (Eastern Cooperative Oncology
patients were more frequently ECOG performance status 0 to 1
Group [ECOG], National Cancer Institute of Canada [NCIC], Mayo Clinic,
Princess Margaret Hospital, Southwest Oncology Group [SWOG], and
(64% vs 57%; P
.001) and more likely to have ISS stage I (39%
University of Arkansas for Medical Sciences [UAMS]). Informed consent
vs 26%; P
.001), but less often intermediate (stage II: 35%
and approval by the local institutional review board (IRB) were fulfilled as
versus 39%; P
.001) or advanced ISS stage (stage III: 27% vs
requested at the time of patient enrollment at each participating center.
34%; P
.001). In addition, young patients presented less often
Patients were started on therapy between 1981 and 2002, and part of the
with the adverse prognostic factors low serum albumin (
35 g/L
information collected was previously used as basis for the generation of the
[
3.5 g/dL]) and high
2-microglobulin (
3.5 mg/dL]) serum
International Staging System (ISS).7 Survival status and date of last
levels (33% vs 41% and 45% vs 59%; P
.001 and P
.001,
follow-up were available for 10 750 patients. A total of 23 of those patients
respectively). Likewise, low hemoglobin (
10 g/dL; 37% versus
were excluded due to unknown age, and 178 were excluded because life
tables for their countries were not available, leaving 10 549 patients for
41%; P
.006), elevated CRP (24% versus 29%; P
.007), and
inclusion in this analysis. A total of 7765 patients received conventional
increased serum creatinine (
2 mg/dL; 15% vs 17%; P
.028)
chemotherapy as first-line treatment, and 2784 patients were subjected to
were less common in the patients younger than 50 years. All other
high-dose therapy with planned autologous stem-cell transplantation.
prognostically relevant laboratory variables investigated, including
The 730 patients who received high-dose treatment as second or later
serum calcium, LDH, bone marrow plasma cell infiltration, and
line of therapy were included in the conventional therapy arm. Of the
hematologic variables, did not differ significantly between the
10 549 patients, 7413 (70%) had been enrolled into clinical trials. The
2 groups. Frequency of IgA isotype was slightly lower (21% vs
median age of patients enrolled in clinical trials was 60 years, and that of
25%; P
.001) and that of light chain myeloma was slightly
the other patients was 63 years. Median follow-up was 3.25 years
(maximum, 19.21 years).
higher (13% vs 10%; P
.002) in the young age cohort.
Standard criteria were applied for diagnosis of multiple myeloma.8
The group of young patients was further split into a subgroup of
Patients with smouldering (asymptomatic) myeloma, amyloidosis, and
very young patients (
40 years of age) and a subgroup of patients
monoclonal IgM-related disorders were not included.
aged 40 to less than 50 years. Table 2 shows a comparison of those
In addition to these cited data, the following information was available:
parameters, which were found to differ between these age groups.
date of start of therapy; sex; ethnicity; race; performance status; hemoglo-
The patients younger than 40 years of age are even more likely to
bin level; platelet count; level and type of paraprotein; and serum levels of
be male (67%), plus have better performance status and lower/
calcium, creatinine, albumin, LDH,
2-microglobulin, and C-reactive
better staging.
protein (CRP). Stage was assessed according to the ISS and the Durie-
Salmon system. Furthermore, the percentage of bone marrow plasma
Median follow-up was 3.25 years (maximum, 19 years) in the
cell infiltration and the number of osteolytic lesions was recorded. In
entire cohort, 4.09 years (maximum, 19.07 years) in the young
522 patients, conventional cytogenetics was available. Del 13 was assessed
patients, and 3.08 years (maximum, 19.21 years) in the patients
by conventional cytogenetics in 454 patients and by fluorescence in situ
aged 50 years or older. Relative excess risk of death was
hybridization (FISH) in 373 patients.
significantly higher in older patients (median adjusted for relative
The chi-square test was used to determine significant prognostic factors
survival, 3.7 years vs 5.2 years; RER, 1.26; 95% confidence
that distinguish younger from older patients. A maximum likelihood model
interval [CI], 1.12-1.42; P
.001), but did not differ between
was used to estimate relative excess risk (RER) for younger versus older
males and females in the respective groups (median [males vs
patients treated with conventional or high-dose treatment, using a general-
ized linear model approach with Poisson error structure using exact survival
females],
50 years, 3.7 years vs 3.7 years; RER, 1.05, 95% CI,
times and collapsed data, as described by Dickman et al.9 To determine
0.996-1.116; P
.07; median
50 years, 5.2 years vs 4.7 years;
these estimates, the observed survival was adjusted by dividing by life
RER, 0.98, 95% CI, 0.09-1.12; P
.81; Figure 1A,B).
expectancy depending on age, sex, year of diagnosis, and nationality.
Better outcome in the younger cohort was seen in all 3 ISS
Relative survival adjustment was done in order to compare survival
stages (Figure 1C) and was independent of sex. Better ECOG
between young and old, while taking the normal mortality expectations of
performance status (
1) was associated with significantly ex-
respective populations into account. Life tables of estimated population
tended survival, both in the younger (median, 5.5 years vs
mortality rates for the country of each treating institution were obtained
4.2 years; RER, 0.74; 95% CI, 0.64-0.84; P
.001), and in the
from the Human Mortality Database.10 Estimates of overall survival within
age groups were produced using the Kaplan-Meier method,11 and were
older cohort (median, 4.2 years vs 2.8 years; RER, 0.67; 95% CI,
compared using the log-rank test.12 Cox regression analysis13 was used to
0.63-0.71; P
.001; Figure 1D). This important interaction be-
develop a multivariate model of prognostic factors using a stepwise
tween younger age and stage as well as performance status was
approach considering those factors that were associated univariately with
most obvious in patients treated with conventional therapy (Figure
survival with a P value of .01 or less. The final model was then adjusted for
1Ci,Di), where it was statistically significant versus in those
relative survival to estimate the RER for each prognostic factor.
patients treated with high-dose therapy (Figure 1Cii,Dii), for whom
it was not statistically significant.
Relative excess risk of death was significantly higher after
Results
conventional treatment in the older cohort (median, 3.3 years vs
4.5 years; RER, 1.43; 95% CI, 1.32-1.55; P
.001; Figure 2A).
Median age of all 10 549 patients combined was 60 years. Of these,
This was also reflected by a significantly higher observed
1689 (16%) patients were younger than 50 years. Of those, most
10-year survival rate (19% vs 8%; log-rank P
.001) in the
(1377 [82%] of 1689) were between 40 to younger than 50 years of
younger patients.

---

From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on May 14, 2008. For personal use
only.
BLOOD, 15 APRIL 2008 VOLUME 111, NUMBER 8
BETTER OUTCOME IN YOUNG PATIENTS WITH MYELOMA
4041
Table 1. Patient characteristics, laboratory parameters, and cytogenetic findings in patients younger than 50 years and patients 50 years or older
Age category
Factor
Younger than 50 y, no. (%)
At least 50 y, no. (%)
P
Male
1023/1689 (61)
5014/8860 (57)
.002
Performance status 2
562/1582 (36)
3603/8328 (43)
.001
ISS
Stage I
492/1267 (39)
1790/6776 (26)
.001
Stage II
438/1267 (35)
2675/6776 (39)
.001
Stage III
337/1267 (27)
2311/6776 (34)
.001
Durie-Salmon stages I or II
612/1530 (40)
3669/7731 (47)
.001
Stage I
108/1333 (8)
494/6168 (8)
.910
Stage II
307/1333 (23)
1612/6168 (26)
.019
Stage III
918/1530 (60)
4062/7731 (53)
.001
Subtype A
1422/1676 (85)
7198/8800 (82)
.003
IgG
924/1538 (60)
4853/8091 (60)
.943
IgA
318/1538 (21)
2009/8091 (25)
.001
IgD
43/1538 (3)
251/8091 (3)
.522
Light chain only
197/1538 (13)
824/8091 (10)
.002
Measurable M-protein
1091/1340 (81)
6695/7754 (86)
.001
More than 3 lytic lesions
617/1292 (48)
3457/7423 (47)
.431
No bone lesions
293/1387 (21)
1756/8000 (22)
.492
2M
3.5 mg/dL ( 0.2975 M)
613/1377 (45)
4141/7061 (59)
.001
Albumin
3.5 g/dL
458/1396 (33)
3276/7912 (41)
.001
HGB
10 g/dL
596/1614 (37)
3465/8539 (41)
.006
Creatinine
2 mg/dL ( 76.8 M)
240/1594 (15)
1484/8573 (17)
.028
Platelets
(130
103) L
152/1420 (11)
984/8168 (12)
.148
Calcium
10 mg/dL ( 2.5 mM)
481/1445 (33)
2652/7870 (34)
.762
CRP 0.8 mg/dL or more
169/695 (24)
1099/3740 (29)
.007
Bone marrow plasma cells 33% or more
892/1544 (58)
4877/8250 (59)
.325
LDH above normal
158/600 (26)
888/3365 (26)
.977
Where conventional units of measure are given in column 1, SI units follow in parentheses.
High-dose chemotherapy with autologous stem cell transplanta-
older patients, respectively. The percentage of young patients
tion resulted in a higher relative excess risk of death in the older
enrolled during different time periods for treatment with conven-
patients (median survival, 5.7 years) compared with the younger
tional therapy decreased from 94.2% in the period between 1981
patients (median survival, 7.5 years; RER, 1.17; 95% CI, 1.01-
and 1987 to 21.3% in the years between 1999 and 2002 (P
.001),
1.36; P
.04; Figure 2B). Similarly, the observed 10-year survival
while the proportion of those subjected to high-dose therapy
rate was significantly higher in the younger patients (43% vs 29%;
increased from 5.7% to 78.7% (P
.001; Table 3). The respective
log-rank P
.005). Relative survival was similar in the subgroup
figures for older patients were 98.8% to 40.1% (P
.001) for conven-
of patients aged 40 to less than 50 years versus that of very young
tional therapy, and 1.2% to 59.9% (P
.001) for high-dose therapy.
patients, both after conventional chemotherapy (4.4 years vs
Analysis of patient characteristics by different time periods of
4.7 years; Figure 2C) and after autologous transplantation
enrollment (1981-1986, 1987-1992, 1993-1998, and 1999-2002)
(7.3 years vs 7.5 years; RER estimates, 1.09 and 0.93, respectively;
revealed a significant improvement of most risk factors over time
Figure 2D). The 10-year survival rates were also similar, both after
(Table 4). This effect was almost exclusively seen in patients aged
conventional (21% vs 19%; P
.37) and after high-dose treatment
50 years and older (Table S1, available on the Blood website; see
(44% vs 38%; P
.76 by log-rank test).
the Supplemental Materials link at the top of the online article),
Conventional therapy was given to 994 (58.9%) of the
while in the younger cohort, no variation of the frequency of poor
1689 patients aged younger than 50 years and to 6771 (76.4%) of
prognostic features over time of enrollment was observed. Compari-
the older patients, while high-dose therapy was administered to
son of relative survival between different time periods of enroll-
695 (41.1%) of the younger patients and to 2089 (23.6%) of the
ment revealed a significant improvement in outcome for patients
receiving conventional therapy during the period between 1999 and
2002 (median relative survival not reached vs 3.3 years for the
Table 2. Clinical and laboratory features, which showed significant
different frequencies between the very young (< 40 years old) and
earlier periods; P
.001) compared with earlier enrollment peri-
the young (40 to < 50 years old) patients
ods (Figure 3A). In patients treated with high-dose therapy, relative
Age category
survival remained constant during the entire period of enrollment
Younger than
40 to younger
(Figure 3B). Both comparisons remain valid even if censoring at
Factor
40 y
than 50 y
P
2 or 4 years.
Male
208/312 (67)
815/1377 (59)
.015
Conventional cytogenetic analysis was available in 522 patients
Performance status 2
87/296 (29)
475/1286 (37)
.014
and showed no difference in the frequency of any cytogenetic
ISS stage II
63/219 (29)
375/1048 (36)
.047
abnormality (Table 5). Likewise, no significant difference in the
Durie-Salmon subtype A
252/310 (81)
1170/1366 (86)
.053
proportion of patients with a del 13, determined either by conven-
Platelets less than 130
109/L
36/247 (15)
116/1173 (10)
.030
tional cytogenetics (454 patients) or by FISH (373 patients), was
Data are number with factor/number with valid data for factor (%)
noted in the 2 age cohorts.

---

From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on May 14, 2008. For personal use
only.
4042
LUDWIG et al
BLOOD, 15 APRIL 2008 VOLUME 111, NUMBER 8
Figure 1. Cumulative relative survival in the entire sample of 10 549 patients stratified by age (A), age and sex (B), age and ISS stage (C), and age and performance status (D)
in all patients, in patients treated with conventional therapy stratified by age and stage (Ci) and age and performance status (Di), and in patients treated by high-dose therapy
stratified by age and stage (Cii) and age and performance status (Dii). Inserts show median values adjusted for relative survival and P values.

---

From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on May 14, 2008. For personal use
only.
BLOOD, 15 APRIL 2008 VOLUME 111, NUMBER 8
BETTER OUTCOME IN YOUNG PATIENTS WITH MYELOMA
4043
Figure 2. Cumulative relative survival in patients treated with conventional therapy (A) and high-dose therapy (B) in patients younger than 50 years or 50 years and older and in
patients younger than 40 years or 40 years and older (C,D). Inserts show median values adjusted for relative survival and P values.
All factors with no more than 15% of values missing (Table 1) were
platelet count (
130
109/L) were identified as independent risk
tested in a Cox regression analysis for their prognostic relevance (data
factors for short survival both in patients treated by conventional or
not shown). Parameters that in univariate analysis correlated with
high-dose therapy. In patients started on conventional therapy, older age,
survival with a significance level of P less than or equal to .01 were then
performance status, presence of serum M-protein, low hemoglobin
considered in a multivariate analysis. Only patients with nonmissing
(
10 g/dL), and bone marrow plasma cell infiltration (
33%) were
values on all factors were included in the multivariate analysis, reducing
recognized as additional independent prognosticators for poor outcome
the actual number of patients analyzed to 3484 (45%) for those treated
(Table 6).
with conventional chemotherapy and to 1654 (59%) for those subjected
to high-dose therapy. Overall survival between the patients included and
those excluded from the multivariate analysis was comparable taking
Discussion
differences by region and time period into account. Of the factors
included in multivariate analysis, both higher ISS and Durie-Salmon
The most important finding in this study on 10 549 patients with
stage, absence of IgA isotype, higher creatinine (
2 mg/dL) and low
multiple myeloma was the significant differences in the presenting
Table 3. Proportion of patients younger than 50 years old versus older than 50 years old treated with either conventional or high-dose
therapy during different time periods
Time period, no. (%)
Treatment
1981 to 1987
1988 to 1992
1993 to 1998
1999 to 2002
Younger than 50 y
Conventional therapy
197 (94.2)
455 (83.9)
299 (40.6)
43 (21.3)
High-dose therapy
12 (5.7)
87 (16.1)
437 (59.4)
159 (78.7)
50 y or older
Conventional therapy
1.107 (98.8)
3.223 (97.4)
2.003 (60.0)
438 (40.1)
High-dose therapy
13 (1.2)
86 (2.6)
1.336 (36.4)
654 (59.9)
*Chi-square test for equal proportions; all P values were less than .001.

---

From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on May 14, 2008. For personal use
only.
4044
LUDWIG et al
BLOOD, 15 APRIL 2008 VOLUME 111, NUMBER 8
Table 4. Change of patient characteristics by time period of enrollment
Cohort, no. with factor/no. with valid data for factor (%)
Factor
1981 to 1987
1988 to 1992
1993 to 1998
1999 to 2002
P
Male
642/1120 (57)
1855/3309 (56)
1898/3339 (57%)
619/1092 (57%)
.870
Performance status 2
532/1093 (49)
1389/3229 (43)
1274/2959 (43%)
408/1047 (39%)
.001
ISS
Stage I
131/718 (18)
639/2622 (24)
794/2607 (30)
226/829 (27)
.001
Stage II
270/718 (38)
1056/2622 (40)
1004/2607 (39)
345/829 (42)
.225
Stage III
317/718 (44)
927/2622 (35)
809/2607 (31)
258/829 (31)
.001
Durie-Salmon stages I or II
418/961 (43)
1546/3052 (51)
1278/2719 (47)
427/999 (43)
.001
Stage I
31/657 (5)
195/2306 (8)
182/2273 (8)
86/932 (9)
.007
Stage II
83/657 (13)
605/2306 (26)
650/2273 (29)
274/932 (29)
.001
Stage III
543/961 (57)
1506/3052 (49)
1441/2719 (53)
572/999 (57)
.001
Subtype A
835/1117 (75)
2671/3301 (81)
2790/3310 (84)
902/1072 (84)
.001
IgG
559/1011 (55)
1864/2969 (63)
1799/3091 (58)
631/1020 (62)
.001
IgA
231/1011 (23)
742/2969 (25)
797/3091 (26)
239/1020 (23)
.191
IgD
48/1011 (5)
93/2969 (3)
97/3091 (3)
13/1020 (1)
.001
Light chain only
138/1011 (14)
229/2969 (8)
333/3091 (11)
124/1020 (12)
.001
Measurable M-protein
894/1029 (87)
2284/2603 (88)
2686/3120 (86)
831/1002 (83)
.002
More than 3 lytic lesions
388/854 (45)
1258/2772 (45)
1354/2834 (48)
457/963 (47)
.264
No bone lesions
200/953 (21)
659/2943 (22)
684/3110 (22)
213/994 (21)
.798
2M
3.5 mg/dL ( 0.2975 M)
515/724 (71)
1674/2636 (64)
1467/2790 (53)
485/911 (53)
.001
Albumin
3.5 g/dL
488/1084 (45)
1308/3131 (42)
1112/2828 (39)
368/869 (42)
.010
HGB
10 g/dL
410/1093 (38)
1267/3119 (41)
1339/3263 (41)
449/1064 (42)
.127
Creatinine
2 mg/dL ( 176.8 M)
244/1103 (22)
596/3175 (19)
487/3249 (15)
157/1046 (15)
.001
Platelets
(130
103) L
115/1084 (11)
333/3133 (11)
377/2918 (13)
159/1033 (15)
.001
Calcium
10 mg/dL ( 2.5 mM)
404/1053 (38)
915/2791 (33)
986/3020 (33)
347/1006 (34)
.004
CRP 0.8 mg/dL or more
7/33 (21)
312/1103 (28)
529/1872 (28)
251/732 (34)
.010
Bone marrow plasma cells 33% or more
665/1032 (64)
1810/3049 (59)
1832/3141 (58)
570/1028 (55)
.001
LDH above normal
63/195 (32)
182/616 (30)
491/1939 (25)
152/615 (25)
.034
Where conventional units of measure are given in column 1, SI units follow in parentheses.
features between young and older patients. Young patients presented
P
.001), and increased steadily during the period patients were
with a significantly lower ISS stage and consequently had less fre-
enrolled into the various trials (Table 4). A similar, albeit less
quently elevation of
2-microglobulin and reduction of low serum
pronounced increase was seen for older patients reflecting the
albumin levels (Table 1). In addition, significantly fewer younger
change in treatment practice with increasing usage of high-dose
patients presented with poor performance status, anemia, renal impair-
therapy also in older patients during recent decades.
ment, or increased CRP levels. Older patients, in contrast, had a greater
Young age was found to be significantly associated with longer
prevalence of less favorable prognostic factors. Hence, both a lower ISS
survival, both after conventional therapy (median, 4.5 years vs
stage at diagnosis and overall better prognostic factors seem to account
3.7 years; P
.001; Figure 2A) and high-dose therapy (median,
for the superior survival in young patients treated with high-dose therapy
7.5 years vs 5.7 years; P
.04; Figure 2B). Similar results with
after correction for differences in life expectancies, with age remaining
high-dose therapy were recently reported by the Nordic Myeloma Study
an independent risk factor for patients treated with conventional therapy
Group.15 They observed significantly longer survival after high-dose
(Table 6). Another relevant finding of this study is the low proportion of
therapy in patients younger than 60 years compared with those aged 60
young patients observed in the entire group of patients studied, a
to 64 years (66 months vs 50 months; P
.001), although response
phenomenon that had been addressed in some prior studies.3,4,14 In our
rates were similar in both cohorts. The data were, however, not corrected
investigation, 16% of the patients were younger than 50 years, 3% were
for differences in general life expectancy between these age groups.
younger than 40 years, and 0.26% were younger than 30 years.
Other studies such as the analysis of the data of International Blood and
The proportion of young patients treated with high-dose therapy
Bone Marrow Registry16 in patients aged younger than 60 years and 60
was almost twice as high (41.1%) as that of older patients (23.6%;
years and older, and data from Little Rock17 in patients aged younger
Figure 3. Cumulative relative survival in patients
treated during different times of enrollment. (A) Rela-
tive survival of conventionally treated patients was signifi-
cantly longer in those enrolled between 1999 and 2002
compared with patients enrolled earlier (P
.001).
(B) Relative survival in patients treated with high-dose
therapy was similar during the different time periods of
enrollment. Inserts show median values adjusted for
relative survival and P values.

---

From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on May 14, 2008. For personal use
only.
BLOOD, 15 APRIL 2008 VOLUME 111, NUMBER 8
BETTER OUTCOME IN YOUNG PATIENTS WITH MYELOMA
4045
Table 5. Cytogenetic findings in patients younger than 50 years of
favorable prognostic factors in the younger patients (Table S2) over
age versus those 50 years and older
the various time periods might mainly explain why survival did not
Age category, no. with factor/no. with
improve during the last enrollment phase in patients treated with
valid data for factor (%)
high-dose therapy (Figure 3B). As follow-up was significantly
Factor
Younger than 50 y
At least 50 y
P
shorter in the young cohort (P
.001), the impact of recent
Any clonal CA
30/116 (26)
117/406 (29)
.533
improvements in second-line treatment and supportive care on
Del13 by cytogenetics
17/109 (16)
45/345 (13)
.499
survival may only become apparent after longer follow-up.
Del13 by FISH
32/53 (60)
150/320 (47)
.069
A recent population based study from Sweden reported an improve-
CA indicates cytogenetic abnormality.
ment in 1-year relative survival ratios over 4 calendar periods from
1973 to 2003 in all age groups of patients with multiple myeloma.18
Information about treatment, however, was not available in indi-
than 65 years or 65 years and older, in contrast, did not reveal significant
vidual patients. The 5- and 10-year survival ratios increased only in
differences in survival between younger and older patients. Selection of
particularly fit elderly patients and/or shorter follow-up in the latter 2
patients younger than 60 and 70 years. A similar increase in 5- and
studies may explain the favorable outcome of these comparisons.
10-year relative survival was recently found for the United States
Another interesting finding is the high 10-year observed sur-
analyzing the Surveillance, Epidemiology, and End Results (SEER)
vival rate observed in both the younger and older patients (43% vs
database.19 In accordance with the report from Sweden, improve-
29%; log-rank P
.005) after high-dose chemotherapy. The
ment in survival was only seen in patients younger than 70 years,
10-year survival rates were also significantly higher in the younger
with highest gains observed in those younger than 50 years of age.
patient cohort (19% vs 8%; P
.001) subjected to conventional
The similar relative and actual 10-year survival (26% vs
chemotherapy for first-line treatment. These figures are impressive,
24%; P
.57 by the log-rank test) in the subgroup of very
given the fact that data collection for this study ended before
young patients aged younger than 40 years and in the young
widespread use of thalidomide and the introduction of bortezomib
patients aged between 40 and less than 50 years is noteworthy
and lenalidomide.
(Figure 2C,D) and prompted us to combine both groups for
The proportion of patients with favorable prognostic factors
further analysis. Nevertheless, the very young patient group
increased during the entire enrollment period from 1982 to 2002,
presented with slightly lower frequency of poor ECOG perfor-
with significantly more patients presenting with lower ISS stage
mance status (
2) and ISS stage II (Table 2), but high-dose
and better performance status in the later enrollment periods (Table
therapy was given to a similar proportion of patients of the very
4). This effect was almost exclusively seen in the older patients
young and young cohort (41.5% vs 39.4%; chi-squared P
.49).
(Table S1) and might be the main reason for the significant
Blade et al previously reported a 10-year survival rate of 13% in
improvement in survival of the patients treated with conventional
patients aged younger than 40 years and of 31% in a small series
therapy during the latest enrollment period (1999-2002) compared
of patients aged younger than 30 years.20
with those enrolled earlier (1982-1998; Figure 3A). Further, better
Significantly more young patients were male compared with
therapy at relapse, with some patients receiving thalidomide and a
older patients. The preponderance of multiple myeloma in male
few even receiving bortezomib as salvage treatment, greater usage
patients is well known, but our data are surprising because a male
of stem cell transplantation after relapse from conventional therapy,
predominance was found in 67% of the very young (younger than
and improved supportive care also might have contributed to the
40 years) and in 59% of the patients aged 40 to younger than 50 years
increase in survival. The absence of an increase in almost all
compared with 57% in those older than 50 years. Experimental mineral
Table 6. RER for factors that were found to correlate independently with survival in multivariate analysis
Factor
Level
RER
95% CI
P
Conventional therapy
ISS stage (reference stage I)
Stage II
1.26
1.12-1.41
ISS stage (reference stage I)
Stage III
1.53
1.34-1.74
.001
Performance status
2
vs 0-1
1.31
1.20-1.43
.001
Durie-Salmon stage
III vs I or II
1.24
1.14-1.36
.001
Platelets
130
109/L vs
130
109/L
1.38
1.21-1.56
.001
Bone marrow plasma cell
33% vs
33%
1.23
1.12-1.34
.001
Age
50
yvs
50 y
1.24
1.08-1.41
.001
Hemoglobin
100 vs
100 g/L
1.14
1.04-1.25
.006
IgA isotype
Present vs absent
1.20
1.06-1.36
.001
Creatinine
176.8 Mvs
176.8 M
1.20
1.36-1.07
.003
Serum M protein
Measurable vs not measurable
0.79
0.68-0.92
.002
High-dose therapy
ISS stage (reference stage I)
Stage II
1.56
1.23-1.97
ISS stage (reference stage I)
Stage III
2.00
0.52-2.63
.001
Platelets
130
109/L vs
130
109/L
1.72
1.35-2.21
.001
Durie-Salmon stage
III vs I or II
1.32
1.08-1.61
.007
IgA isotype
Present vs absent
1.31
1.07-1.60
.008
Creatinine
176.8 Mvs
176.8 M
1.38
1.06-1.79
.015
Age*
50
yvs
50 y
1.17
0.95-1.43
.122
Patients treated with conventional chemotherapy: n
3484 with nonmissing values on all factors, 45% of 7765 patients; patients treated with high-dose therapy: n
1654
patients with nonmissing values for all factors, 59% of 2784 patients.
*Not significant, but included for comparison.

---

From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on May 14, 2008. For personal use
only.
4046
LUDWIG et al
BLOOD, 15 APRIL 2008 VOLUME 111, NUMBER 8
oil­induced plasmocytoma occurs more frequently in male mice and
analysis to 3484 (45%) for those treated with conventional therapy and
2-methoxyestradiol, an estrogen derivate, has been shown to exert
to 1654 (59%) subjected to high-dose therapy. As overall survival rates
antimyeloma activity both in cell lines and in myeloma-bearing
between the patients included and those excluded from the multivariate
mice.21 Whether increased androgenic sex hormone levels in young
analysis were comparable after correcting for differences by region and
males do account for the preponderance of multiple myeloma in
by time period, there seems to be no reason to assume that the patient
very young male adults, however, remains speculative as yet.
characteristics were different. In patients treated with conventional
Overall survival, however, did not differ between male and female
chemotherapy, 10 parameters were identified as independent risk factors
patients, which is in contrast to several other cancers such as
for shortened survival by multivariate analysis (Table 6). Only 5 of
chronic myeloid leukemia,22 acute myeloid leukemia,23 and others
these, namely ISS and Durie-Salmon stage, platelet counts, creatinine,
that show significantly longer survival in female patients.
and IgA isotype were also identified as independent risk factors in
The frequency of cytogenetic abnormalities was very similar in the
patients treated with high-dose therapy (Table 6). Hence, high-dose
younger-than-50-years cohort and in the older-age cohort (26% vs 29%;
therapy seems to overcome the negative impact of some of the
P
.533). Of note, del 13 was found in 16% by conventional
unfavorable prognostic factors, including age. The latter finding may be
cytogenetics and in 60% by FISH in the young patients, and correspond-
biased by the mode of patient selection for high-dose therapy, as only
ingly in 13% and 47% in the older patients (P
.499 and P
.069,
older patients deemed to be healthy enough for this procedure actually
respectively; Table 5). This agrees with previous findings obtained in
will undergo transplantation. The favorable prognostic importance of a
2 smaller studies that did not reveal any association between cytogenetic
lower ISS stage is expected and has been confirmed in other studies.30
aberrations and age in a cohort of 75 patients24 and in another group of
The finding of an IgA isotype, increased serum creatinine, and low
172 patients.25 In the latter study, similar frequencies of chromosomal
platelet counts has previously been reported as prognostically rel-
aberrations have been observed in 3 cohorts of patients with different
evant,31,32 but the role of these factors is now firmly established due to
age definitions (younger than 45 years, 45 to 70 years, and older than
the large number of patients included in our study.
70 years) and in all ISS stages. This is in disagreement with a report that
In conclusion, patients with myeloma younger than 50 years of
indicated a decreasing frequency of IgH translocations with increasing
age had significantly longer age-adjusted survival both after
age.26 In our cohort, other parameters such as LDH and bone marrow
conventional and high-dose therapy (5.4 and 7.5 years, respec-
plasma cell infiltration, which also reflect characteristics of the biology
tively) in relation to older patients (3.7 and 5.7 years, respectively).
of the myeloma cell population, were evenly distributed between the
Given the fact that thalidomide and other new drugs were not
2 age cohorts, indicating an absence of a major difference in the biology
available for most patients, the 10-year survival rate was remark-
of the myeloma clone between young or older patients. A similar
ably high in young patients after conventional (19%) and high-dose
conclusion has already previously been proposed in a study that
therapy (43%). The major factors accounting for this improved
compared survival in patients younger or older than 65 years. Differ-
outcome of young patients were presentation with a lower ISS
ences in absolute survival between these groups disappeared after
stage at diagnosis and other more favorable prognostic features.
correction for differences in life expectancy and calculation of
relative survival.27
It is also noteworthy that serum calcium and serum creatinine
Acknowledgment
did not differ between the young and very young patients. Blade et
al reported in an analysis of 72 patients with myeloma younger than
This study was supported by the International Myeloma Founda-
40 years a relatively high incidence of hypercalcemia (30%) and
tion (Los Angeles, CA).
renal impairment (creatinine level,
177
M; 29%), which was
not seen in our patients. They also observed a high frequency
(32%) of light chains as the only paraprotein in their young
patients, which agrees to some extent with our findings, which also
Authorship
revealed a higher, but less pronounced prevalence of light chain
disease in patients aged 50 years or less (13% vs 10%; P
.002).
Contribution: H.L. and B.G.M.D. submitted, analyzed, and interpreted
As in our study, other laboratory characteristics were similar to
data and drafted the manuscript. V.B. and J.C. analyzed data and
those of the general myeloma population. In spite of the high
commented on the manuscript. I.T., R.A.K., J.B., R.F., MD, K.S.,
incidence of initial hypercalcemia in their patients, median overall
J.S.M., J.W., J.-L.H., M.B., M.B., A.P., B.B., C.S., M.C., P.R.G., M.A.,
survival was nevertheless found to be 54 months.4
and P.S. submitted and interpreted data, and commented on the
The selection of patients for the current analysis was based upon
manuscript. D.J. interpreted data and commented on the manuscript.
enrollment into clinical studies, including high-dose therapy; hence, the
A complete list of the participating study groups can be found in
median age overall is lower than the general population of patients with
Document S1, available on the Blood website; see the Supplemen-
myeloma, with a median age of 65 to 70 years at presentation.28,29
tal Materials link at the top of the online article.
However, a higher median age of the entire population would, if
Conflict-of-interest disclosure: The authors declare no compet-
anything, have increased the difference in presenting features, which
ing financial interests.
were noted as an important finding in these various analyses.
Correspondence: Heinz Ludwig, Department of Medicine,
Multivariate analysis was conducted in patients with nonmissing
Wilhelminenspital, Montleartstr. 37, 1160 Vienna, Austria; e-mail:
values on all factors, reducing the number of patients included in the
heinz.ludwig@wienkav.at.
References
1. Wisloff F, Andersen P, Andersson TR, et al. Has
2. Bergsagel D. The incidence and epidemiology of
4. Blade J, Kyle RA, Greipp PR. Presenting features
the incidence of multiple myeloma in old age
plasma cell neoplasms. Stem Cells. 1995;13:1-9.
and prognosis in 72 patients with multiple my-
been underestimated? The Myeloma project of
3. Corso A, Klersy C, Lazzarino M, Bernasconi C. Mul-
eloma who were younger than 40 years. Br J
health region I in Norway. Euro J Haematol. 1991;
tiple myeloma in younger patients:the role of age as
Haematol. 1996;93:345-351.
47:33-337.
prognostic factor. Ann Haematol. 1998;76:67-73.
5. Bacher U, Kern W, Schnittger S, Hiddemann W,

---

From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on May 14, 2008. For personal use
only.
BLOOD, 15 APRIL 2008 VOLUME 111, NUMBER 8
BETTER OUTCOME IN YOUNG PATIENTS WITH MYELOMA
4047
Haferlach T, Schoch C. Population-based age-
16. Reece DE, Bredeson C, Perez WS, et al. Autolo-
gender, age, disease phase, culture time, and
specific incidences of cytogenetic subgroups of
gous stem cell transplantation in multiple my-
cytokine stimulation. Eur J Haematol. 2002;68:
acute myeloid leukemia. Haematologica. 2005;
eloma patients
60 versus
60 years of age.
345-353.
90:1502-1510.
Bone Marrow Transplant. 2003;32:1135-1143.
25. Sagaster V, Kaufmann H, Odelga V, et al. Chro-
6. Gajdos C, Tartter PI, Bleiweiss IJ, Bodian C,
17. Siegel DS, Desikan KR, Mehta J, et al. Age is not
mosomal abnormalities of young multiple my-
Brower ST. Stage 0 to stage III breast cancer in
a prognostic variable with autotransplants for
eloma patients (
45 years) are not different from
young women. Am Coll Surg. 2000;190:523-529.
multiple myeloma. Blood. 1999;93:51-54.
those of other age groups and are independent of
7. Greipp PR, San Miguel J, Durie BG, et al. Inter-
stage according to the International Staging Sys-
18. Kristinsson SY, Landgren O, Dickman PW, et al.,
national Staging System for multiple myeloma.
tem. Eur J Haematol. 2007;78:227-234.
Patterns of survival in multiple myeloma: a popu-
J Clin Oncol. 2005;23:3412-3420.
lation-based study of patients diagnosed in Swe-
26. Ross FM, Ibrahim AH, Vilain-Holmes A, et al. UK
8. Durie BGM, Salmon S. Recent advances in
den from 1973 to 2003. J Clin Oncol. 2007;20:
Myeloma Forum. Age has a profound effect on
Haematology. Edinburgh, United Kingdom:
1993-1999.
the incidence and significance of chromosome
Churchill Livingston; 1977.
abnormalities in myeloma. Leukemia. 2005;19:
19. Brenner H, Gondos A, Pulte D Recent major im-
9. Dickman P, Sloggett A, Hills M, Hakulinen T. Re-
1634-1642.
provement in long-term survival of younger pa-
gression models for relative survival. Stat Med.
tients with multiple myeloma. Blood. Prepub-
27. Ludwig H, Fritz E, Friedl HP. Epidemiologic and
2004;23:51-64.
lished September 27, 2007, as DOI 10.1182/
age-dependent data on multiple myeloma in Aus-
10. University of California, Berkeley (CA), Max Planck
blood-2007-08-104984.
tria. J Natl Cancer Inst. 1982;68:729-733.
Institute for Demographic Research (Berlin, Ger-
28. Kyle RA, Gertz MA, Witzig TE, et al. Review of
20. Blade J, Kyle RA, Greipp PR. Multiple myeloma
many). Human Mortality Database. Available at:
1027 patients with newly diagnosed multiple my-
in patients younger than 30 years: report of 10
www.mortality.org. Accessed March 31, 2006.
eloma. Mayo Clin Proc. 2003;78:21-33.
cases and review of the literature. Arch Intern
11. Kaplan EL, Meier P. Nonparametric estimation
Med. 1996;156:1463-1468.
29. Ries LAG, Eisner MP, Kosary CL, et al. SEER
from incomplete observations. J Am Stat Assoc.
Cancer Statistics Review, 1975-2002, National
1958;53:457-481.
21. Dingli D, Timm M, Russell SJ, Witzig TE, Raijku-
Cancer Institute. Bethesda MD. Available at:
mar SV. Promising preclinical activity of 2-
12. Mantel N. Evaluation of survival data and two
http://seer.cancer.gov/csr/1975_2002/results_
methoxyestradiol in multiple myeloma. Clin
new rank order statistics arising in its consider-
single/sect_01_table.11_2pgs.pdf. Accessed
Cancer Res. 2002;8:3948-3954.
ation. Cancer Chemother Rep. 1966;50:163-170.
January 17, 2007.
13. Cox DR. Regression models and life tables. J R
22. Berger U, Maywald O, Pfirrmann M, et al.; Ger-
30. Krejci M, Buchler T, Hajek R, et al. Prognostic fac-
Stat Soc B. 1972;34:187-220.
man CML-Study Group. Gender aspects in
tors for survival after autologous transplantation:
chronic myeloid leukemia: long-term results from
14. Blade J, Kyle RA. Multiple myeloma in young pa-
a single centre experience in 133 multiple my-
randomized studies. Leukemia. 2005;19:984-989.
tients: clinical presentation and treatment ap-
eloma patients. Bone Marrow Transplant. 2005;
proach. Leuk Lymphoma. 1998;30:493-501.
23. Bennett JM, Young ML, Andersen JW, et al. Long-
35:159-164.
15. Lenhoff S, Hjorth M, Westin J, et al. Impact of age
term survival in acute myeloid leukemia: the East-
31. Cavo M, Galieni P, Zuffa E, et al. Prognostic vari-
on survival after intensive therapy for multiple my-
ern Cooperative Oncology Group experience.
ables and clinical staging in multiple myeloma.
eloma: a population-based study by the Nordic
Cancer. 1997;80:2205-2209.
Blood. 1989;74:1774-1780.
Myeloma Study Group. Br J Haematol. 2006;133:
24. Nilsson T, Lenhoff S, Turesson I, et al. Cytoge-
32. Kyle RA. Multiple myeloma: a review of 869
389-396.
netic features of multiple myeloma: impact of
cases. Proc Mayo Clinic. 1975;50:29-40.

---