Bone Marrow Transplantation (2016) 51, 1449–1455

© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0268-3369/16
www.nature.com/bmt

ORIGINAL ARTICLE
Autologous stem cell transplant for multiple myeloma patients
70 years or older
E Muchtar1, D Dingli1, S Kumar1, FK Buadi1, A Dispenzieri1, SR Hayman1, RC Wolf2, DA Gastineau1, R Chakraborty1,3, WJ Hogan1,
N Leung1,4, P Kapoor1, MQ Lacy1, SV Rajkumar1 and MA Gertz1

Autologous stem cell transplant (Auto-SCT) is increasingly used in older patients with multiple myeloma (MM), despite lack of phase
3 trials in this age-defined population. For 207 consecutive MM patients who underwent Auto-SCT and were 70 years or older at
transplant (study cohort), data were analyzed and compared with a younger cohort (1764 Auto-SCT patients o70 years old). The
proportion of Auto-SCT in the older patients increased from 7.8% of all transplants in 1998–2006 to 12.9% in 2007–2015. Sixty
percent of patients required stem cell mobilization with chemotherapy or plerixafor. Full-dose melphalan conditioning was given to
55% of the older patients compared with 93% of the younger patients (P o 0.001). Older patients were more likely to be
hospitalized (64% vs 55%; P = 0.01), but hospitalization duration was comparable. For newly diagnosed patients, median PFS was
33.5 months for the older cohort and 33.8 months for the younger cohort (P = 0.91), and median overall survival was 6.1 and 7.8
years, respectively (P = 0.11). Presumably, a smaller fraction of patients, age 70–76, is selected for Auto-SCT, but the benefits are
comparable to those seen for younger patients. Reduced-dose melphalan was given to approximately half the patients to avoid
excessive toxicity.

Bone Marrow Transplantation (2016) 51, 1449–1455; doi:10.1038/bmt.2016.174; published online 4 July 2016

INTRODUCTION Stem cell mobilization

Several randomized controlled trials have shown that autologous
stem cell transplant (Auto-SCT) is superior to conventional
chemotherapy in multiple myeloma (MM).1–3 As such, Auto-SCT
became the standard of care, and MM is the most common
indication for Auto-SCT.4 Its superiority has been reconfirmed in
the era of novel agents.5 However, most trials restricted eligibility
for Auto-SCT to patients younger than 65 years. With a median
age at diagnosis of MM is 66 years,6 this age restriction limits
accessibility to Auto-SCT for a large proportion of patients.
Nevertheless, several transplant centers have reported the
feasibility and safety of Auto-SCT in MM patients older than 65
years.7–9 Survival benefit was demonstrated in some studies
through case–control matching7,10,11 or longitudinal design.12,13
In this study, we evaluated the outcome of stem cell
mobilization and transplant for MM patients 70 years or older.
To assess changes in efficacy and toxicity over time, the study
cohort was divided into two time periods, 1998 to 2006 and 2007
to 2015.
MATERIALS AND METHODS
From the institutional transplant registry, 207 consecutive MM patients
who were 70 years or older at Auto-SCT (study cohort) were identified. The
study cohort was compared with 1764 patients from the registry who were
younger than 70 years at Auto-SCT (median age, 59 years; interquartile
range (IQR), 53–64 years). All patients had provided informed consent for
the use of their medical records. The Mayo Clinic Institutional Review Board
approved this study.
Mobilization and transplant management at our institution have been
previously described.14,15 All mobilizations were performed with G-CSF SC
(10 μg/kg/day). G-CSF was given alone or after cyclophosphamide (CY)
(1.5 g/m2 daily for two consecutive days) or with plerixafor (routinely
available since 2009). The goal was to collect 3 × 106 progenitor cells/kg for
single transplant, given the age of the patients (achieved in 98.5% of
patients; all patients yielded more than 2 × 106 cells/kg).
Conditioning regimen, stem cell reconstitution and supportive
care
Full-dose melphalan (200 mg/m2) or reduced-dose melphalan (140 mg/m2)
was given at the physician's discretion, depending on patient general
fitness, co-morbidities and renal function. Auto-SCT was performed as an
outpatient procedure, requiring a caregiver and a stay near the hospital
throughout the transplant period. Patients were followed up daily in a
designated outpatient unit. Patients were admitted for uncontrolled fever,
poor intake, intractable pain from mucositis that necessitated parenteral
medication, decrease in performance status or arrhythmia.
Patients returned on day 100 post transplant for reevaluation, which
included serum and urine studies and bone marrow examination.
Response evaluation
Response was determined according to the International Myeloma
Working Group response criteria16 and was evaluated before and after
Auto-SCT. The best response after Auto-SCT was used for post-Auto-SCT
response evaluation.

1
Division of Hematology, Mayo Clinic, Rochester, MN, USA; 2Pharmacy Services, Mayo Clinic, Rochester, MN, USA; 3Hospitalist Services, Essentia Health-St Joseph’s Center,
Brainerd, MN, USA and 4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA. Correspondence: Dr MA Gertz, Division of Hematology, Mayo Clinic, 200 First
St SW, Rochester, MN 55905, USA.
E-mail: gertz.morie@mayo.edu.
Received 15 March 2016; revised 9 May 2016; accepted 17 May 2016; published online 4 July 2016
 Autotransplant in older multiple myeloma patients
E Muchtar et al
1450
Statistical analysis
Data were reported as median and IQR or as mean. The χ2 test and Fisher's
exact test were used to compare differences between continuous
variables, and the Wilcoxon signed rank test was used for nonparametric
group comparisons.
PFS and overall survival (OS) were calculated with the Kaplan–Meier
method; differences between groups were calculated with the log-rank
test. Multivariate analysis for factors affecting survival was performed with
the Cox proportional hazards model. We included the following variables
in the univariate and multivariate models for PFS and OS: sex, transplant
period, disease status (newly diagnosed or relapsed disease), response
before Auto-SCT, creatinine clearance at transplant, International Staging
System (ISS) stage, bone marrow plasma cells at diagnosis, melphalan
conditioning dose and response after transplant.
All statistical analysis was performed with JMP software (SAS Institute Inc.)
with statistical significance set at Po0.05.
RESULTS
Table 1 displays the characteristics of the study cohort divided
into two equal periods: 1998–2006 and 2007–2015. Among all
transplants, the proportion of Auto-SCT in patients 70 years or
older increased from 7.8% in 1998–2006 to 12.9% in 2007–2015
(P o 0.001). The median age of patients was 72 years, similar
between periods (P = 0.69), but a larger percentage of women
underwent transplant in 2007–2015 (41.7%) than in 1998–2006
(26.8%) (P = 0.04). Seventy-six percent of patients underwent Auto-
SCT for newly diagnosed disease, while 24% were exposed to
more than one line of treatment before Auto-SCT, with no
difference between periods (P = 0.35) or when compared with
patients younger than 70 years (P = 0.28). Achievement of a partial
response or better before transplant was similar in 1998–2006 and
2007–2015 (60.7% vs 71.5%, respectively; P = 0.14). However, the
rate of a very good partial response (VGPR) or better before Auto-
SCT nearly doubled between periods (16.1% vs 30.5%, respec-
tively; P = 0.03).
Stem cell collection
The median time from diagnosis to stem cell collection was
6.3 months (range, 0.2–219 months). Stem cell collection was
performed with G-CSF alone in 40% of patients, G-CSF and
plerixafor in 39% of patients, and G-CSF in combination with CY in
21% of patients. When mobilization was more than 12 months
after diagnosis, patients were more likely to require two
mobilizing agents compared with mobilization within 12 months
after diagnosis (72.7% vs 57.2%, respectively; P = 0.09).
G-CSF/CY mobilization was more frequent in 1998–2006
compared with 2007–2015 (43% vs 12.5%; Po 0.001). Seventy-
seven percent of patients who were mobilized with G-CSF/CY had
no response to their last regimen. With G-CSF/plerixafor mobiliza-
tion, the median number of plerixafor doses was 2 (range, 1–5).
Patients who received prior radiotherapy were more likely to
require plerixafor compared with patients who did not receive
prior radiotherapy (27.5% vs 13.4%; P = 0.01). The median number
of apheresis sessions was 2, similar to the younger cohort, but
fewer apheresis sessions were performed on average in the study
cohort compared with the younger cohort (mean, 2.3 vs 3.1 days,
respectively; Po 0.001). The number of apheresis sessions was
lower in 2007–2015 compared with 1998–2006 (mean, 2.1 vs
2.6 days; P = 0.02).
The median yield of CD34+ cells was lower in patients 70 years
or older compared with the younger cohort (5.6 × 106/kg vs
9.4 × 106/kg; Po0.001). The median CD34+ cell yield was higher with
G-CSF/CY (7.5 × 106/kg) than with G-CSF/plerixafor (5.4 × 106/kg)
or G-CSF alone (4.9 × 106/kg) (Po0.001).
Conditioning and stem cell infusion
The median time from diagnosis to transplant was 7.4 months
(range, 3.1–219 months), similar to the younger cohort
(7.2 months; P = 0.41). Conditioning with full-dose melphalan
(200 mg/m2) was given to 55% of patients compared with 93% in

Table 1. Baseline characteristics

Variable Entire cohort (N = 207) Transplant period P-value

1998–2006 (n = 56) 2007–2015 (n = 151)

Age, median (range), years 72 (70–76.1) 72 (70–75.8) 72 (70–76.1) 0.69

Male, n (%) 129 (62.3) 41 (73.2) 88 (58.3) 0.04
eGFR at transplant, median (range), mL/min/1.73 m2 70 (6–149) 69 (6–128) 73 (17–149) 0.16
M-spike, median (25–75% IQR), g/dL 2.8 (1.2–4.3) 3.5 (1.6–4.6) 2.3 (1–4) 0.02
BMPCs at diagnosis, median (25–75% IQR), % 40 (0–100) 40 (23–71) 41 (22–80) 0.28
Labeling index at diagnosis, median (25–75% IQR), % 0.8 (0.2–1.9) 0.5 (0.2–1.4) 1 (0.4–2.1) 0.09
BMPCs pretransplant, median (25–75% IQR), % 13 (0–75) 16 (2–28) 5 (1–15) 0.008
Labeling index pretransplant, median (25–75% IQR), % 1.03 (0–11) 0.2 (0–1.1) 0.5 (0–1.6) 0.12

ISS at diagnosis, % 0.43

1 26.4 20.5 28.4
2 44.5 52.3 41.7
3 29.1 27.2 29.9

FISH (n = 121) 0.34

Intermediate riska, % 14 17 14
High riskb, % 16 0 17

Disease status before Auto-SCT 0.34

Newly diagnosed, % 75.8 80.4 74.2
Relapsed/refractory, % 24.2 19.6 25.8
Prior lines of treatment, median (range), n 1 (1–6) 1 (1–5) 1 (1–6) 0.19
Response before Auto-SCT ( ⩾ PR), % 68.6 60.7 71.5 0.14
Abbreviations: Auto-SCT = autologous stem cell transplant; BMPC = bone marrow plasma cell; eGFR = estimated glomerular filtration rate; ISS = International
Staging System; IQR = interquartile range; PR = partial response. aIntermediate risk was considered t(4;14) or 1q amplification (or both). bHigh risk was
considered to be any of the following: del(17p)/17 monosomy, t(14;16), t(14;20), or del(1p).

Bone Marrow Transplantation (2016) 1449 – 1455 © 2016 Macmillan Publishers Limited, part of Springer Nature.

the younger cohort (P o0.001). Of the study patients who
received reduced-dose melphalan, 30% had an eGFR of
50 mL/min/1.73 m2 at transplant; four of them were receiving
hemodialysis at transplant. In a multivariate analysis performed on
the study cohort, the following features were associated with the
use of reduced-dose melphalan: age (odds ratio (OR), 1.2 for each 1-
year increment; 95% CI, 1.01–1.4; P = 0.02), eGFR o50 mL/min/
1.73 m2 (OR, 9.2; 95% CI, 3.5–30; Po0.001), harvested CD34+ cells
(OR, 0.85 for each increment in 1 × 106 CD34+ cells/kg yield; 95% CI,
0.75–0.93; Po0.001) and adjusted diffusing capacity of the lung for
carbon monoxide (OR, 0.97 for each percentage increment; 95% CI,
0.94–0.99; P = 0.01). Patients were infused with a median of 4.6 × 106
CD34+ cells/kg (IQR, 3.9 × 106 to 5.8 × 106); 69% were infused with
all their collected cells.
Engraftment and transfusion requirements
Median time to neutrophil engraftment was 14 days (IQR,
13–16 days) and to platelet engraftment 15 days (IQR,
14–17 days). Time to engraftment did not differ between patients
who received full-dose melphalan and patients who received
reduced-dose melphalan (for neutrophil engraftment, P = 0.96; for
platelet engraftment, P = 0.44). Time to neutrophil and platelet
engraftment did not differ between the study cohort and the
younger cohort.
In the 30 days after stem cell infusion, patients were transfused
with a median of 2 units of packed RBC and 2 units of platelets
(IQR, 1–3 for each). The median number of transfusions was higher
in 1998–2006 than in 2007–2015 (3 vs 2 units of RBC, P o 0.001;
3 vs 2.5 platelet transfusions, P = 0.005). The number of transfu-
sions did not differ between full and reduced conditioning doses.
Post-transplant complications
Neutropenic fever and bacteremia. Neutropenic fever occurred in
70% of patients, in a smaller percentage in the 2007–2015 than in
the 1998–2006 (60.2% vs 89.3%; P o 0.001). Bacteremia was
documented in 29.5% of patients, with a lower rate in 2007–2015
compared with 1998–2006 (22.5% vs 48.2%; P o0.001). The rate of
bacteremia in the study cohort did not differ from that in the
younger cohort (29.8%; P = 0.92). Gram-positive bacteria were
recovered from 75% of the positive blood cultures; Gram-negative
bacteria were recovered from 32.8% of the positive cultures.
Cardiac arrhythmia. Atrial arrhythmia, primarily atrial fibrillation
or flutter with rapid ventricular response, developed in 22.4% of
patients. Arrhythmias occurred at a median of 8 days (IQR,
4–10 days) after stem cell infusion. No difference was noted in the
rate of arrhythmia between the two periods (P = 0.79). The
frequency of arrhythmia was not influenced by the conditioning
dose (P = 0.76). Only 12% of patients who had arrhythmia during
transplant had a prior history of a similar event. Neutropenic fever
(risk ratio, 2.3; 95% CI, 1.1–4.6; P = 0.01) and forced expiratory
volume in 1 s (FEV1) less than 90% (risk ratio, 1.2; 95% CI,
1.01–1.38; P = 0.02) were significantly associated with a risk of
cardiac arrhythmia. Most cases resolved with medical treatment.
Table 2. Depth of response after autologous stem cell transplant
Variable
Overall
1998–2006 vs 2007–2015
Reduced-dose melphalan vs full-dose melphalan
Interval between diagnosis and SCT (p12 vs 412 months)
eGFR (X30 vs o 30)
Abbreviations: eGFR = estimated glomerular filtration rate; PR = partial response; sCR = stringent complete response; SCT = stem cell transplant; VGPR = very
good partial response.
© 2016 Macmillan Publishers Limited, part of Springer Nature.
Autotransplant in older multiple myeloma patients
E Muchtar et al
1451
Other complications. Fourteen patients (7%) had engraftment
syndrome; Clostridium difficile colitis developed in 12 patients
(6%), but none required intervention other than antibiotic
treatment. Six patients had venous thromboembolic events, and
all were treated medically.
Two patients (1%) died within 100 days after transplant. One
patient, conditioned with full-dose melphalan, died of CMV
pneumonitis on day 25. The other patient, conditioned with
reduced-dose melphalan, died of failure to thrive at day 95. In
comparison, the treatment-related mortality rate for the younger
cohort was 1.4% (P = 0.6).
Hospitalization
Sixty-four percent of patients were hospitalized during transplant
(two patients solely for the lack of a caregiver). In comparison, 55%
of the younger cohort required hospitalization (P = 0.01). The
median length of stay for the hospitalized patients in the study
cohort was 8 days (IQR, 4–12 days), similar to the median for the
younger cohort (7 days; IQR, 5–13 days; P = 0.52). Patients in
2007–2015 had a shorter median hospital stay compared with
patients in 1998–2006 (6 vs 9 days; P o0.001). Intensive care unit
admission occurred at similar rates for these 2 periods (18.5 vs
16.7%; P = 0.78), and 69% of intensive care unit admissions were
for observation for cardiac arrhythmias. On a multivariate analysis,
the factors associated with prolonged hospitalization (47 days)
were occurrence of neutropenic fever (OR, 3.2; 95% CI, 1.4–7.6;
P = 0.004), induction of cardiac arrhythmia (OR, 2.6; 95% CI, 1.3–5.4;
P = 0.01), transplant period 1998–2006 (OR, 2.9; 95% CI, 1.5–6;
P = 0.002) and eGFR less than 50 mL/min/1.73 m2 (OR, 3; 95% CI,
1.3–7; P = 0.01).
Response and survival
Response data are presented in Table 2. The overall response rate
after Auto-SCT was 93.2%, with no significant difference between
the two periods (P = 0.62). The response rate was higher in the full-
dose melphalan subgroup compared with the reduced-dose
melphalan (96.5% vs 89.1%; P = 0.03). Stringent complete response
(sCR) was reached by 27.3% of patients after Auto-SCT. On
multivariate analysis, the only parameter that affected the ability
to obtain sCR after Auto-SCT was achievement of VGPR or better
before transplant (OR, 17.3; 95% CI, 6.7–50.6; P o0.0001), with full-
dose melphalan only marginally associated with a higher sCR
probability after Auto-SCT (OR, 2.4; 95% CI, 0.9–6.5; P = 0.08).
The study population consisted of newly diagnosed patients
and patients with relapsed disease, so for homogeneity, survival
curves were restricted to newly diagnosed patients. In the older
cohort, median PFS was 33.5 months, which was comparable to
PFS in the younger cohort (33.8 months; P = 0.91). The median OS
in the older cohort was 6.1 years compared with 7.8 years in the
younger cohort (P = 0.11) (Figure 1). See Supplementary Figure for
OS and PFS for newly diagnosed patients by transplant period.
In the study cohort, achievement of at least VGPR before Auto-SCT
was associated with marginally improved PFS and OS compared
with less than VGPR before SCT (for PFS: median, 45.2 vs 31.5 months;
PR or better, % P-value VGPR or better, % P-value sCR, % P-value
93.2 61.0 27.3
94.5 vs 92.7 0.62 65.5 vs 59.3 0.42 20 vs 30 0.14
89.1 vs 96.5 0.03 52.2 vs 68.1 0.01 21.7 vs 31.9 0.1
94.2 vs 87.9 0.22 61.4 vs 60.6 0.93 26.9 vs 30.3 0.69
100 vs 92.8 0.2 81.8 vs 59.8 0.12 27.3 vs 27.3 40.99
Bone Marrow Transplantation (2016) 1449 – 1455
 Autotransplant in older multiple myeloma patients
E Muchtar et al
1452
a with only a trend to a survival advantage (median 125.6 vs
1.0
Age ≥ 70 y 85.5 months; P = 0.13).
Age < 70 y
0.8
Probability of PFS

DISCUSSION
0.6
This study is the largest single-center report on the use of Auto-
SCT in elderly patients. It is also characterized by a higher age
0.4
threshold than most other studies, thus showing more convin-
Median PFS: cingly the feasibility and safety of Auto-SCT in the elderly. We have
0.2 Age ≥ 70 y, 33.5 mo
Age < 70 y, 33.8 mo
shown that patients aged 70 years and up to 76 selected for Auto-
Log-rank P =0.91 SCT have non-inferior PFS and OS compared with younger
0.0 patients. In addition, while infection control is better in elderly
0 24 48 72 96 120 144 168 192 216 patients in recent years, the rate of cardiac arrhythmia remains
PFS, months after diagnosis high and unchanged over time, raising the need for preventive
No. at risk
measures.
157 82 23 13 4 2 1 0 0 0
Despite the lack of randomized data for Auto-SCT in elderly
1,279 668 249 113 65 33 15 5 2 0 patients, its application in the elderly has increased because of the
growing experience with Auto-SCT in general, improved suppor-
tive care and better stem cell mobilization.13,17 Another important
b 1.0
Age ≥ 70 y factor is the introduction of reduced-dose conditioning, shown to
Age < 70 y be better tolerated in elderly patients and still yield beneficial
Probability of survival

0.8 results, comparable to conditioning with melphalan 200 mg/m2.1

0.6
0.4
Median OS:
0.2 Age ≥ 70 y, 6.1 y
Age < 70 y, 7.8 y
Log-rank P =0.11
0.0
0 2 4 6 8 10 12
OS, years after diagnosis
No. at risk
157 112 63 35 20 7 1
1,279 940 599 370 249 138 61
Figure 1. Kaplan–Meier survival curves for patients with a new
diagnosis who were in the older cohort (⩾70 years) or younger
cohort ( o70 years). (a) PFS. (b) Overall survival (OS).
P = 0.05) (for OS: median, 9.3 vs 5.8 years; P = 0.13). After Auto-SCT,
patients who achieved sCR had better PFS and OS than those who
achieved less than sCR (for PFS: median, 80.8 vs 29.7 months;
Po 0.001) (for OS: median, 10.1 vs 5.9 years; P = 0.009) (Figure 2).
In a univariate analysis, the following variables were significantly
associated with a decreased PFS: male sex, transplant period
1998–2006, relapsed disease state, attainment of less than VGPR
before Auto-SCT and attainment of less than sCR after transplant
(Table 3). In a univariate analysis, inferior OS was associated with
the following variables: male sex, transplant period 1998–2006, ISS
stage III (vs ISS stages I or II), achievement of less than VGPR before
Auto-SCT and achievement of less than sCR after Auto-SCT. In a
multivariate analysis, shorter PFS was predicted by male sex,
transplant period 1998–2006, relapsed disease state and attain-
ment of less than sCR after transplant. In comparison, predictors
for shorter OS in a multivariate analysis were transplant period
1998–2006 and ISS stage III.
Maintenance therapy
Maintenance therapy was given for 24.1% of patients following
auto-SCT, with similar rates for newly diagnosed and relapsed
patients (25 and 21.3%, respectively; P = 0.6). Maintenance regi-
mens were mainly bortezomib-based (45%) or lenalidomide-based
(39%). Maintenance was given exclusively in the 2007–2015 period.
When analysis was restricted to the 2007–2015 period, maintenance
treatment, as compared with observation, was associated with
improved PFS (median 60.7 vs 29.1 months, respectively; P = 0.01),
We previously showed that improved survival of MM patients
was seen mainly among patients older than 65 years, while
younger patients showed no survival improvement.18 This
selective outcome improvement is probably associated with both
the increased use of Auto-SCT in elderly patients in our institution
as well as the introduction of novel agents that broadly extended
the treatment options in this age-defined population. Eight
percent of all transplants in 1998–2006 was in patients 70 years
14 16 18 20 22 or older, and this rate increased to about 13% in 2007–2015, a
relative increment of 65%. We have found comparable outcomes
in PFS and OS between patients 70 years or older and patients
0 0 0 0 younger than 70 years. Those outcomes were shown specifically
26 9 2 1 for newly diagnosed patients, who comprise most of the
patients in the present study. PFS improved by a similar
magnitude for both age groups between the two periods
(1998–2006 vs 2007–2015) (Supplementary Figure). OS by
transplant period also improved for both groups but was more
pronounced for patients ⩾ 70 years, suggesting better patient
selection and peri-transplant management of this challenging
group of patients.
Only 40% of patients underwent mobilization with G-CSF alone,
whereas the remaining patients required mobilization with either
cyclophosphamide (21%) or plerixafor (39%). Such a high
requirement for a second mobilization agent has not been
reported for younger MM patients and likely reflects the effect of
age on mobilization capacity.19,20 Cyclophosphamide was used to
mobilize stem cells for refractory disease in earlier years to reduce
the precollection tumor burden. In comparison, plerixafor was
used in late mobilizations (412 months from diagnosis) and in
patients who had previously received radiotherapy. For mobiliza-
tion, the CD34+ yield with G-CSF/plerixafor was similar to that with
G-CSF alone (6.23 × 106/kg vs 5.66 × 106/kg). As evidenced from
randomized controlled trials demonstrating a higher CD34+ yield
when plerixafor is added to G-CSF, the comparable CD34+ yield
between these subgroups probably reflects patient selection for
plerixafor. In contrast, patients who received G-CSF/CY yielded
more CD34+ cells, as previously reported.21,22
Elderly patients are more likely to face toxic effects from the
transplant.13 Bacteremia rates decreased from 1998–2006 to
2007–2015, reflecting enhanced infection control measures.
Although hospitalization occurred more frequently for the older
cohort compared with the younger cohort, the duration of
hospitalization was similar between groups, suggesting that the
severity of major complications was similar between groups,
which is also reflected in a comparable treatment-related
mortality. However, nearly half the older patients received

Bone Marrow Transplantation (2016) 1449 – 1455 © 2016 Macmillan Publishers Limited, part of Springer Nature.
 Autotransplant in older multiple myeloma patients
E Muchtar et al
1453
a 1.0 b 1.0
VGPR or better before SCT sCR after SCT
Less than VGPR before SCT Less than sCR after SCT
0.8 0.8
Probability of PFS

Probability of PFS
Median PFS:
sCR after SCT, 80.8 mo
0.6 0.6 Less than sCR after SCT, 29.7 mo
Log-rank P <0.001
0.4 0.4

Median PFS
0.2 VGPR or better, 45.2 mo 0.2
Less than VGPR, 31.5 mo
Log-rank P =0.05
0.0 0.0
0 24 48 72 96 120 144 168 0 24 48 72 96 120 144 168
PFS, months after diagnosis PFS, months after diagnosis
No. at risk No. at risk
49 28 10 5 1 1 0 45 31 13 7 2 2 0
108 54 13 8 3 2 1 110 51 10 6 2 1 1

c 1.0 d 1.0
VGPR or better before SCT sCR after SCT
Less than VGPR before SCT Less than sCR after SCT

Probability of survival
0.8 0.8
Probability of survival

0.6 0.6

0.4 0.4
Median OS: Median OS:
0.2 VGPR or better, 9.3 y 0.2 sCR after SCT, 10.1 y
Less than VGPR, 5.8 y Less than sCR after SCT, 5.9 y
Log-rank P =0.13 Log-rank P =0.009
0.0 0.0
0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14
OS, years after diagnosis OS, years after diagnosis
No. at risk No. at risk
49 34 17 9 6 3 1 45 34 18 9 7 5 1
108 78 46 26 14 4 0 110 78 45 26 13 2 0

Figure 2. Kaplan–Meier survival curves for subgroup analysis for patients with a new diagnosis who were in the older cohort (⩾70 years).
(a) PFS according to response before stem cell transplant (SCT). (b) PFS according to response after SCT. (c) Overall survival (OS) according to
response before SCT. (d) OS according to response after SCT. sCR = stringent complete response; VGPR = very good partial response.

Table 3. Univariate and multivariate Cox regression models for PFS and OS

Variable PFS OS

Univariate Multivariate Univariate Multivariate

HR P-value HR P-value HR P-value HR P-value

Male 1.7 (1.2–2.5) 0.006 1.6 (1.1–2.4) 0.01 1.6 (1.05–2.6) 0.04 1.4 (0.9–2.4) 0.17
1998–2006 vs 2007–2015 1.5 (1.02–2.1) 0.03 1.5 (1.0–2.2) 0.048 2.1 (1.3–3.2) o0.001 1.8 (1.1–3.0) 0.02
Relapsed diseasea 2.6 (1.7–3.8) o0.001 3 (2.0–4.5) o 0.001 0.8 (0.5–1.2) 0.33
Less than VGPR before Auto-SCT 1.9 (1.3–3.0) 0.002 1 (0.7–1.7) 0.87 2 (1.1–3.8) 0.01 1.1 (0.6–2.3) 0.82
eGFR o30 mL/min/1.73 m2 1.5 (0.7–4.2) 0.34 1.5 (0.6–3.1) 0.38
ISS stage III vs I or II 1.2 (0.7–1.8) 0.46 2 (1.2–3.2) 0.008 1.9 (1.1–3.2) 0.01
BMPC at diagnosisb 1.3 (0.6–2.9) 0.45 1.2 (0.4–3.1) 0.75
Reduced-dose melphalan conditioning 1.3 (0.9–1.8) 0.21 1.3 (0.8–1.9) 0.26
sCR after Auto-SCT 0.3 (0.2–0.5) o0.001 0.3 (0.2–0.4) o 0.001 0.3 (0.2–0.6) o0.001 0.5 (0.2–1.1) 0.09
Abbreviations: Auto-SCT = autologous stem cell transplant; BMPC = bone marrow plasma cell; eGFR = estimated glomerular filtration rate; HR = hazard ratio;
ISS = International Staging System; OS = overall survival; sCR = stringent complete response; VGPR = very good partial response. aFor patients with relapsed
disease, PFS was considered from time of progression before Auto-SCT; OS was considered from time of diagnosis. bPer change over the entire range.

reduced-dose melphalan conditioning, compared with only 7% of
patients younger than 70 years. Therefore, decreasing the dose of
melphalan for conditioning may reduce excessive toxicity in the
elderly. The melphalan dose was adjusted because of reduced
eGFR in only 30% of patients. Therefore, the conditioning dose
should not be determined solely by renal function. In the past
years, awareness to elderly patients' frailty has led to formation of
geriatric indices for treatment considerations.23,24 Whether these
indices can help in guidance of the conditioning dose selection is
a relevant question. In our view it will require development of a

© 2016 Macmillan Publishers Limited, part of Springer Nature. Bone Marrow Transplantation (2016) 1449 – 1455
 Autotransplant in older multiple myeloma patients
E Muchtar et al
1454
specific index, as the current indices are generalized to the elderly
population, thus may not be sensitive enough to appropriately
select patients who are transplant eligible.
One of the important complications observed in the present
study was the development of cardiac arrhythmia. This required
hospitalization for rate control, including intensive care unit
admission for monitoring. Only 12% of those patients had a prior
history of arrhythmia; therefore, prediction of patients at risk of
arrhythmia is challenging. A reduced FEV1 was a predictor for atrial
arrhythmias, which has also been shown to be a risk factor for
atrial fibrillation in the general population.25,26 Cardiac toxicity
from melphalan, high prevalence of fever, electrolyte imbalance
and change in regular medications (such as temporarily halting
β-blocker for hypotension) are potential drivers for the cardiac
arrhythmias development in the peri-transplant period. A high
rate of atrial fibrillation has been reported with Auto-SCT in an
inpatient setting27 and among patients with renal impairment.28
We observed no change in this complication rate over the years;
this finding emphasizes that, unlike infectious complications, the
prevention of cardiac arrhythmias has not been adequately
addressed. Investigation of other risk factors for arrhythmia is
warranted to promote preventive measures in a more focused
manner. Drug therapy, such as amiodarone or β-blockers, is
probably warranted for prevention in high-risk patients, but the
appropriate selection for this intervention needs to be clarified.
Our study limitations include its retrospective design, lack of
comparable data among patients younger than 70 (such as rate of
several complications, including cardiac arrhythmia) and lack of
standardized approach in the selection of the melphalan dose.
In conclusion, with proper selection Auto-SCT is safe in MM
patients 70 to 76 years old. Like younger patients who have been
studied in randomized controlled trials, older patients appear to
benefit from Auto-SCT. Reduced-dose melphalan is required in
many of these older patients to minimize toxicity. Cardiac
arrhythmia was common and required urgent intervention in
many instances; because the incidence of cardiac arrhythmia has
been stable over time, a preventive strategy in patients deemed
high risk for this complication is warranted and requires further
study. In light of these results a randomized trial comparing
standard treatment with auto-SCT in elderly patients eligible for
transplant is warranted.
CONFLICT OF INTEREST
SK: Celgene Corp. (consultancy and research funding), Millennium Pharmaceuticals
Inc. (consultancy and research funding), Novartis International AG (research funding),
Onyx Pharmaceuticals Inc. (consultancy and research funding), AbbVie Inc. (research
funding), Janssen Pharmaceuticals, Inc. (consultancy and research funding) and
Bristol-Myers Squibb Co. (consultancy and research funding); AD: Celgene Corp
(research funding), Millennium Pharmaceuticals Inc. (research funding), Pfizer Inc.
(research funding and travel grant) and Janssen Pharmaceuticals Inc. (research
funding); PK: Millennium Pharmaceuticals Inc. (Takeda Pharmaceutical Co. Limited)
(research funding), Celgene Corp. (research funding) and Onyx Pharmaceuticals Inc.
(Amgen Inc.) (research funding); MQL: Celgene Corp. (research funding); MAG:
Celgene Corp (honoraria), Millennium Pharmaceuticals, Inc. (consultancy and
honoraria), Onyx Pharmaceuticals Inc. (honoraria), Novartis International AG
(honoraria) and GlaxoSmithKline PLC (honoraria). The remaining authors declare no
conflict of interest.
AUTHOR CONTRIBUTIONS
EM and MAG designed the study, collected the data, analyzed the data, wrote
the first draft, and approved the final version of the manuscript; DD, SK, FKB,
AD, SRH, WJH, NL, PK, MQL and SVR provided patient management, critically
reviewed the first draft and approved the final version of the manuscript; RCW
and RC collected data, provided critical review and approved the final version of
the manuscript; and DAG provided patient management, collected data,
provided critical review and approved the final version of the manuscript.
Bone Marrow Transplantation (2016) 1449 – 1455
REFERENCES
1 Palumbo A, Bringhen S, Bertola A, Cavallo F, Falco P, Massaia M et al. Multiple
myeloma: comparison of two dose-intensive melphalan regimens (100 vs
200 mg/m2). Leukemia 2004; 18: 133–138.
2 Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K et al. Medical Research
Council Adult Leukaemia Working Party. High-dose chemotherapy with hemato-
poietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348: 1875–1883.
3 Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF et al. Intergroupe
Francais du Myelome. A prospective, randomized trial of autologous bone
marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med
1996; 335: 91–97.
4 Passweg JR, Baldomero H, Peters C, Gaspar HB, Cesaro S, Dreger P et al. European
Society for Blood and Marrow Transplantation EBMT. Hematopoietic SCT in
Europe: data and trends in 2012 with special consideration of pediatric trans-
plantation. Bone Marrow Transplant 2014; 49: 744–750.
5 Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT et al.
Autologous transplantation and maintenance therapy in multiple myeloma.
N Engl J Med 2014; 371: 895–905.
6 Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A et al. Review
of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;
78: 21–33.
7 Winn AN, Shah GL, Cohen JT, Lin PJ, Parsons SK. The real world effectiveness of
hematopoietic transplant among elderly individuals with multiple myeloma.
J Natl Cancer Inst 2015; 107: 1–6.
8 Wildes TM, Finney JD, Fiala M, Gao F, Vij R, Stockerl-Goldstein K et al. High-dose
therapy and autologous stem cell transplant in older adults with multiple
myeloma. Bone Marrow Transplant 2015; 50: 1075–1082.
9 El Cheikh J, Kfoury E, Calmels B, Lemarie C, Stoppa AM, Bouabdallah R et al. Age at
transplantation and outcome after autologous stem cell transplantation in elderly
patients with multiple myeloma. Hematol Oncol Stem Cell Ther 2011; 4: 30–36.
10 Muta T, Miyamoto T, Fujisaki T, Ohno Y, Kamimura T, Kato K et al. Fukuoka Blood
and Marrow Transplant Group (FBMTG). Evaluation of the feasibility and efficacy
of autologous stem cell transplantation in elderly patients with multiple myeloma.
Intern Med 2013; 52: 63–70.
11 Kumar SK, Dingli D, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK et al.
Autologous stem cell transplantation in patients of 70 years and older with
multiple myeloma: results from a matched pair analysis. Am J Hematol 2008;
83: 614–617.
12 McCarthy PL Jr, Hahn T, Hassebroek A, Bredeson C, Gajewski J, Hale G et al. Trends
in use of and survival after autologous hematopoietic cell transplantation in North
America, 1995-2005: significant improvement in survival for lymphoma and
myeloma during a period of increasing recipient age. Biol Blood Marrow Trans-
plant 2013; 19: 1116–1123.
13 Auner HW, Szydlo R, Hoek J, Goldschmidt H, Stoppa AM, Morgan GJ et al. Trends
in autologous hematopoietic cell transplantation for multiple myeloma in Europe:
increased use and improved outcomes in elderly patients in recent years. Bone
Marrow Transplant 2015; 50: 209–215.
14 Gertz MA, Dingli D. How we manage autologous stem cell transplantation for
patients with multiple myeloma. Blood 2014; 124: 882–890.
15 Gertz MA, Ansell SM, Dingli D, Dispenzieri A, Buadi FK, Elliott MA et al. Autologous
stem cell transplant in 716 patients with multiple myeloma: low treatment-related
mortality, feasibility of outpatient transplant, and effect of a multidisciplinary
quality initiative. Mayo Clin Proc 2008; 83: 1131–1138.
16 Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K et al. Inter-
national Myeloma Working Group. International uniform response criteria for
multiple myeloma. Leukemia 2006; 20: 1467–1473.
17 Sharma M, Zhang MJ, Zhong X, Abidi MH, Akpek G, Bacher U et al. Older patients
with myeloma derive similar benefit from autologous transplantation. Biol Blood
Marrow Transplant 2014; 20: 1796–1803.
18 Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S et al. Continued
improvement in survival in multiple myeloma: changes in early mortality and
outcomes in older patients. Leukemia 2014; 28: 1122–1128.
19 Pozotrigo M, Adel N, Landau H, Lesokhin A, Lendvai N, Chung DJ et al. Factors
impacting stem cell mobilization failure rate and efficiency in multiple myeloma
in the era of novel therapies: experience at Memorial Sloan Kettering
Cancer Center. Bone Marrow Transplant 2013; 48: 1033–1039.
20 Morris CL, Siegel E, Barlogie B, Cottler-Fox M, Lin P, Fassas A et al. Mobilization of
CD34+ cells in elderly patients (X70 years) with multiple myeloma: influence of
age, prior therapy, platelet count and mobilization regimen. Br J Haematol 2003;
120: 413–423.
21 Silvennoinen R, Anttila P, Saily M, Lundan T, Heiskanen J, Siitonen TM et al.
A randomized phase II study of stem cell mobilization with cyclophosphamide+G-
CSF or G-CSF alone after lenalidomide-based induction in multiple myeloma.
Bone Marrow Transplant 2015; 51: 372–376.
© 2016 Macmillan Publishers Limited, part of Springer Nature.

22 Lin TL, Wang PN, Kuo MC, Hung YH, Chang H, Tang TC. Cyclophosphamide plus
granulocyte-colony stimulating factor for hematopoietic stem cell mobilization in
patients with multiple myeloma. J Clin Apher (e-pub ahead of print 5 September
2015; doi:10.1002/jca.21421).
23 Hamaker ME, Jonker JM, de Rooij SE, Vos AG, Smorenburg CH, van Munster BC.
Frailty screening methods for predicting outcome of a comprehensive geriatric
assessment in elderly patients with cancer: a systematic review. Lancet Oncol
2012; 13: e437–e444.
24 Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK et al. Geriatric
assessment predicts survival and toxicities in elderly myeloma patients: an
International Myeloma Working Group report. Blood 2015; 125: 2068–2074.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website (http://www.nature.com/bmt)
© 2016 Macmillan Publishers Limited, part of Springer Nature.
Autotransplant in older multiple myeloma patients
E Muchtar et al
1455
25 Johnson LS, Juhlin T, Engstrom G, Nilsson PM. Reduced forced expiratory volume
is associated with increased incidence of atrial fibrillation: the Malmo Preventive
Project. Europace 2014; 16: 182–188.
26 Buch P, Friberg J, Scharling H, Lange P, Prescott E. Reduced lung function and risk of
atrial fibrillation in the Copenhagen City Heart Study. Eur Respir J 2003; 21: 1012–1016.
27 Sureddi RK, Amani F, Hebbar P, Williams DK, Leonardi M, Paydak H et al. Atrial
fibrillation following autologous stem cell transplantation in patients with multiple
myeloma: incidence and risk factors. Ther Adv Cardiovasc Dis 2012; 6: 229–236.
28 St Bernard R, Chodirker L, Masih-Khan E, Jiang H, Franke N, Kukreti V et al. Efficacy,
toxicity and mortality of autologous SCT in multiple myeloma patients with
dialysis-dependent renal failure. Bone Marrow Transplant 2015; 50: 95–99.
Bone Marrow Transplantation (2016) 1449 – 1455