Leukemia (2011), 19
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ORIGINAL ARTICLE
Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs
and bortezomib: A multicenter international myeloma working group study
SK Kumar1, JH Lee2, JJ Lahuerta3, G Morgan4, PG Richardson5, J Crowley6, J Haessler6, J Feather5, A Hoering6, P Moreau7,
X LeLeu8, C Hulin9, SK Klein10, P Sonneveld10, D Siegel11, J Blade´12, H Goldschmidt13, S Jagannath14, JS Miguel15, R Orlowski16,
A Palumbo17, O Sezer18, SV Rajkumar1 and BGM Durie19 on behalf of the International Myeloma Working Group20
1Divison of Hematology, Mayo Clinic, Rochester, MN, USA; 2Division of Hemato-Oncology, Gachon University Gil Hospital,
Incheon, Republic of Korea; 3Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain; 4Department
of Hematology, Royal Marsden Hospital, Sutton, UK; 5Department of Medical Oncology, Division of Hematologic Malignancies,
Dana-Farber Cancer Institute, Boston, MA, USA; 6Cancer Research & Biostatistics, Seattle, WA, USA; 7Division of Hematology,
University Hospital Hotel-Dieu, Nantes, France; 8Service du Maladies du Sang, Hopital Claude Huriez, CHU Lille, France;
9Service D'he´matologie CHU Nancy, France; 10Department of Hematology, Erasmus MC, Rotterdam, The Netherland; 11Medical
Oncology, Hackensack University Medical Center, The Cancer Center, Hackensack, NJ, USA; 12Hematology, Hospital Clinic,
Barcelona, Spain; 13Hematology, University of Heidelberg, Heidelberg, Germany; 14Medical Oncology, Mt. Sinai Cancer
Institute, New York, NY, USA; 15Servico de Hematologia, Hospital Universario de Salamanca, Salamanca, Spain; 16University
of Texas/MD Anderson Cancer Center, Houston, TX, USA; 17Department of Hematology, University of Torino, Torino, Italy;
18Department of Hematology, University of Hamburg, Hamburg, Germany and 19Cedars-Sinai Outpatient Cancer Center at the
Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA
Promising new drugs are being evaluated for treatment of multiple
been the lack of information about the natural history of MM in
myeloma (MM), but their impact should be measured against the
the relapsed patient population. Although this type of informa-
expected outcome in patients failing current therapies. However,
tion is available for patients receiving the older therapies, such
the natural history of relapsed disease in the current era remains
data are lacking for patients relapsing after the new therapies.
unclear. We studied 286 patients with relapsed MM, who were
refractory to bortezomib and were relapsed following, refractory
This information can be beneficial for development of new
to or ineligible to receive, an IMiD (immunomodulatory drug), had
therapies, as early and accurate identification of the most
measurable disease, and ECOG PS of 0, 1 or 2. The date patients
promising treatments can allow prioritization of current clinical
satisfied the entry criteria was defined as time zero (T0). The
trials. Hence, the International Myeloma Working Group
median age at diagnosis was 58 years, and time from diagnosis to
(IMWG) undertook this current study with the aim of determin-
T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment
ing the outcome of patients who have become refractory to
recorded with one or more regimens (median ¼ 1; range 08). The
first regimen contained bortezomib in 55 (26%) patients and an
bortezomib and at least one of the IMiDs. We also wanted to
IMiD in 70 (33%). A minor response or better was seen to at least
assess the types of therapy administered in this patient group and
one therapy after T0 in 94 patients (44%) including Xpartial
the response rates and duration of response to these treatments
response in 69 (32%). The median overall survival and event-free
to establish a context for assessing the results of ongoing trials
survival from T0 were 9 and 5 months, respectively. This study
with new drugs in myeloma.
confirms the poor outcome, once patients become refractory to
current treatments. The results provide context for interpreting
ongoing trials of new drugs.
Leukemia advance online publication, 29 July 2011;
doi:10.1038/leu.2011.196
Patients and methods
Keywords: multiple myeloma; relapse; natural history; survival
Patients were identified by review of medical records at multiple
centers from across the United States, Europe and Asia. Patients
Introduction
had to be refractory to bortezomib (administered either alone or
in combination with other agents), defined as no response (less
Survival of patients with multiple myeloma (MM) has improved
than partial response), or progression on therapy, or progression
during the past decade with the introduction of immunomodu-
within 60 days of stopping a bortezomib-containing regimen, as
latory drugs (IMiDs; thalidomide and lenalidomide), and the
per published consensus criteria. In addition, patients should
proteasome inhibitor bortezomib.110 However, MM remains
have relapsed and/or were refractory, intolerant or ineligible
incurable, and new therapies are required for continued disease
(in the opinion of the treating physician) to receive treatment
control. In fact, several new drugs are currently undergoing
with an IMiD (thalidomide or lenalidomide). We used either one
evaluation, and many appear promising based on initial
of the IMiDs instead of both IMiDs, taking into consideration the
results.5,11 One of the difficulties in interpreting the early results
differences in availability of the two drugs in different parts of
of these newer therapies from the small single-arm studies has
the world. The date the patient met this criteria was defined as
time zero (T0). Given the goal of using these data as a
Correspondence: Dr SK Kumar, Divison of Hematology and Blood and
benchmark for assessing future clinical trial results, we only
Marrow Transplant, Mayo Clinic, 200 First Street SW, Rochester,
included patients who would typically be considered for
MN 55905, USA.
participation in a clinical trial. Hence, patients had to have
E-mail: kumar.shaji@mayo.edu
20
ECOG performance status of 0, 1 or 2, as well as measurable
See Appendix
Received 27 December 2010; revised 30 May 2011; accepted 28
disease at T0 (defined conventionally as a serum M protein
June 2011
X1.0 g/dl or 24 h urine M-protein excretion X200 mg or bone
Outcome in relapsed myeloma
SK Kumar et al
2
marrow plasma cells X30%). Patients with prior allogeneic
dates for the required treatment regimens. All analyses were
stem cell transplantation were excluded from the study.
carried out using SAS version 9.1.3.
Clinical and laboratory data pertaining to the time of
diagnosis and from the time of individual relapses were obtained
from clinical records. The dates of initiation and discontinuation of
Results
each treatment regimen, as well as the reason for discontinuation
were identified, with specific attention to confirmation of use and
Complete data were available on 286 patients (from among 300
discontinuation of IMiDs and bortezomib due to emergence of
patients enrolled) and were included in the current analysis. This
resistance or toxicity. Detailed data collection sheets were devel-
included patients from nine sites (107 patients from three US
oped, which were used at all the study sites for uniformity of data
sites; 115 from five European sites; and 64 from one Asian site).
collection. The data were sent to a centralized area (Cancer Research
The median (range) age for the patient group was 58 years
And Biostatistics, Seattle, WA, USA) for analysis in a de-identified
(3085) at diagnosis and 62 (3587) at time zero, and 176 (62%)
manner. Institutional Review Boards from each site approved the
were male. The median estimated follow-up for the entire
study and the use of patient medical records, and was conducted in
cohort from diagnosis was 5.8 years (95% CI; 5.1, 6.3) and
accordance with the principles of the Declaration of Helsinki.
the median time from diagnosis to T0 was 3.3 years (range,
Response categories were defined according to the EBMT or
0.218.7). The baseline characteristics from diagnosis and from
IMWG criteria, and the response rate was defined as the
T0 are as shown in Table 1. The median number of regimens
proportion of patients achieving at least a partial response, from
among those patients with valid response data. Patients who did
Table 1
Baseline characteristics at diagnosis and at time zero (T0)
not receive a myeloma regimen following time zero were not
included in the response-rate analysis. The response rate and
Factor
N/n (%)
best response were calculated for each regimen used before and
after T
Male
176/286 (62)
0. Duration of response was defined as the length of time
between the date a patient first achieved a partial response or
Median age at diagnosis (range)
58 (3085)
greater response level and the earlier of the dates at which
Serum heavy chain at diagnosis
criteria for progression (defined by EBMT or IMWG criteria)
None
27/250 (1)
were met or the date of death. Patients who did not have a
IgG
155/250 (62)
documented progression after achieving at least a partial
IgA
60/250 (24)
response and who were still alive at last contact were censored
Durie Salmon stage at diagnosis
for duration of response at the date of last contact. Patients who
Stage 1
14/216 (6)
did not achieve a partial response or better following T0, and
Stage 2a
47/216 (22)
patients for whom the date of such response was missing, were
Stage 3a
152/216 (70)
excluded from the duration of response analysis. Duration of
ISS at diagnosis
response was estimated using the KaplanMeier method with
Stage 1
63/208 (30)
the median duration of response summarized.
Stage 2
87/208 (42)
Overall survival (OS) was defined as the length of time
Stage 3
58/208 (28)
between T0 and the date of death. Patients without a recorded
Diagnosis Creatinine 4 ULN
84/212 (40)
death date were censored for OS at their last contact date.
No bone lesions at diagnosis
63/256 (25)
Progression-free survival (PFS) was defined as the length of time
X4 bone lesions at diagnosis
102/256 (40)
between T0 until the earlier of the date at which criteria for
Diagnosis FISH
progression were met or the date of death. Patients who did not
All abnormalities
63/95 (66)
have a documented progression after T0 and who did not have a
del 17p, t(4;14), t(14;16)
21/95 (22)
recorded death date were censored for PFS at their last contact
13q-
41/95 (43)
date. OS and PFS were estimated using the KaplanMeier
t(11;14)
9/95 (9)
method with the median survival durations summarized. Cox
Diagnosis cytogenetic abnormalities
50/132 (38)
regression analysis was performed to determine which prog-
nostic factors at T0 and/or at baseline correlated with improved
Time zero (T0)
OS or PFS from T0. Prognostic factors were dichotomized,
where appropriate, using standard myeloma cutoffs. Prognostic
Median age at T0 (range)
62.5 (3587)
factors with univariate P-values o0.100 were considered for
inclusion in the multivariate model. The multivariate model
ISS at T0
Stage 1
31/172 (18)
used a stepwise selection with an entry level of Po0.10; with
Stage 2
82/172 (48)
backwards elimination set at Po0.05.
Stage 3
59/172 (34)
Time to next treatment (TNT) after T0 was defined as the
length of time between the start of the first regimen following T0
FISH at T0
and the start of the second regimen following T
All abnormalities
30/38 (79)
0. Patients who
started both a first and second regimen following T
del 17p, t(4;14), t(14;16)
9/38 (26)
0, who do not
13q-
13/38 (34)
have recorded start dates for these regimens, were excluded
t(11;14)
3/38 (8)
from this analysis. Patients who did not start a second regimen
following T0 were censored for TNT at the date of last contact.
T0 cytogenetic abnormalities
23/47 (49)
TNT was estimated using cumulative incidence methodology,
Median number of regimens before T0 (range)
4 (1,13)
with the median TNT summarized. Death preceding the start of
At least 1 transplant before T0
178/286 (62)
a second regimen following T
X2 transplants before T0
42/286 (15)
0 was treated as a competing risk.
Additional TNT estimates were generated for subsequent regi-
Abbreviations: FISH, fluorescence in situ hybridization; ISS, International
mens where a sufficient number of patients have recorded start
staging system; n, number with factor; N, number with valid data for factor.
Leukemia
Outcome in relapsed myeloma
SK Kumar et al
3
Table 2
Response rate by regimen number, following time zero (T0)
Drugs included in the regimen
Regimen number following time zero (T0)
12
3
4
5
Number of patients
213
90
49
27
18
Corticosteroids (part of combination)
140 (66)
47 (52)
26 (53)
20 (74)
9 (50)
Cyclophosphamide
66 (31)
22 (24)
10 (20)
6 (22)
3 (17)
Bortezomib
55 (26)
22 (24)
19 (39)
7 (26)
8 (44)
Doxorubicin
43 (20)
11 (12)
6 (12)
1 (4)
3 (17)
Lenalidomide
41 (19)
13 (14)
8 (16)
6 (22)
3 (17)
Melphalan
31 (15)
15 (17)
9 (18)
7 (26)
0 (0)
Thalidomide
29 (14)
15 (17)
7 (14)
3 (11)
2(11)
Etoposide
25 (12)
4 (4)
3 (6)
0 (0)
2 (11)
Cisplatin
22 (10)
6 (7)
3 (6)
0 (0)
2 (11)
Corticosteroids alone
17 (8)
6 (7)
2 (4)
1 (4)
0 (0)
Vincristine
18 (8)
3 (3)
2 (4)
2 (7)
1 (6)
BCNU (Carmustine)
4 (2)
1 (1)
2 (4)
1 (4)
0 (0)
Best response (XPR) (%)
50/213 (24)
17/90 (19)
12/49 (24)
6/27 (22)
1/18 (6)
Best response (XMR) (%)
73/213 (34)
25/90 (28)
14/49 (29)
8/27 (30)
3/18 (17)
Best Response with a regimen
25/106 (24)
6/42 (14)
7/27 (26)
1/14 (7)
0/10 (0)
containing bortezomib, lenalidomide
or thalidomide, % (number of patients)
Best Response with a regimen without
26/107 (24)
11/48 (23)
5/22 (23)
5/13 (38)
1/8 (13)
bortezomib, lenalidomide or thalidomide,
% (number of patients)
Median duration of treatment (months)
1.9
1.3
1.4
1.7
1.9
Abbreviations: MR, minor response; PR, partial response.
before T0 was 4 (range, 113); 81 (41%) patients had three
single agents. Alkylating agents (melphalan and cyclopho-
regimens or less before reaching T0 and 45 (16%) patients had
sphamide) was the most common class of drugs used at this
received 46 regimens by the time they reached T0. The details of
stage of the disease with 97 (46%) patients receiving a regimen
the initial therapy in terms of the drugs used are included in
that contained one of these drugs. Interestingly, 22 (11%) and 25
Supplementary Table 1. In terms of prior therapy, by definition all
(12%) of patients received cisplatin and etoposide, respectively,
patients had previous therapy with bortezomib and were
likely a reflection of the use of regimens such as DT-PACE.
considered refractory to bortezomib. Among them, 188 patients
Nearly a quarter of patients achieved a partial response or
had relapsed on therapy while the remaining patients had either
better to the first regimen used after T0 (50/213, 24%) including
not responded or had relapsed within 60 days of discontinuing the
a very good partial response or better in 7% of the patients.
drug. With respect to the IMiDs, 205 and 79 patients, respectively,
Another 22 (7%) patients had a minor response and 36 (10%)
were refractory to or ineligible for treatment with thalidomide or
had stable disease as their best response to the treatment. Nearly
lenalidomide. Among the thalidomide treated patients, 135
half of the patients (104; 49%) had progressive disease to the first
patients had relapsed on therapy and/or were refractory, 69
line of therapy following T0 or a response was not assessable.
patients had gone off for toxicity and were considered as
The response rates and categories of responses observed are as
intolerant, and one person was missing this information. For the
detailed in Table 3. We also analyzed responses by regimen,
lenalidomide patients, 70 had relapsed on therapy and/or were
based on whether patients received a regimen containing the
refractory, and nine were intolerant. The drug that patients were
newer drugs (bortezomib, lenalidomide or thalidomide) or not.
relapsing on or refractory to immediately before (or closest to) T0
The response rate to the first treatment regimen was 24% among
was bortezomibin 73% and anIMiDin27%.
the 106 patients treated with a regimen containing bortezomib,
lenalidomide or thalidomide compared with 25% among the
107 patients receiving a regimen not containing one of these
Initial therapy following time zero
three drugs (Table 3). Specifically, 12 (22%) of the 55 patients
We first examined the types of therapy that were used
receiving bortezomib as part of the first regimen after T0 had a
immediately following T0. Only 213 patients (74%) had a
response of partial response or better. The breakdown of the
treatment identified in the medical records following T0 and the
response rates and the response categories for a newer drug-
median time to first treatment following T0 was 0.5 months. The
containing regimen and those without these three drugs is
drugs used (alone or in combinations) for the initial treatment of
provided in Supplementary Tables 24. The primary reasons
the relapsed refractory disease are detailed in Table 2. Interest-
for discontinuing the regimens are detailed in Supplementary
ingly, in this group of patients who met the criteria for having
Table 5. The most common reason for discontinuation of a
bortezomib refractory disease, 55 patients (26%) received a
treatment regimen was lack of response or disease progression
bortezomib-containing treatment regimen immediately follow-
followed by adverse event or completion of planned course of
ing T0. Bortezomib alone or with dexamethasone was the most
treatment. A clear reason for discontinuation could not be
common bortezomib-based regimen used (41%) followed by the
ascertained for about 17% of the regimens.
combination of bortezomib, lenalidomide or thalidomide, and
dexamethasone (17%). Thalidomide or lenalidomide was
included in the initial treatment in 70 patients (32%). As would
Subsequent therapies
be expected, corticosteroids were part of the treatment in 157
The subsequent drugs used for treatment within the different
(74%) patients, including 17 (8%) patients receiving steroids as
lines of therapy are detailed in Table 2, along with the best
Leukemia
Outcome in relapsed myeloma
SK Kumar et al
4
Table 3
Best response to regimen, by regimen number, for the initial regimens following time zero
Regimen
1st
2nd
3rd
4th
5th
factor
Number of patients
213
90
49
27
18
Complete response (%)
4/213 (2)
1/90 (1)
0/49 (0)
1/27 (4)
0/18 (0)
Very good partial response (%)
10/213 (5)
2/90 ()
1/49 (2)
2/27 (7)
0/18 (0)
Partial response (%)
36/213 (17)
14/90 (16)
11/49 (22)
3/27 (11)
1/18 (6)
Minor response (%)
22/213 (10)
8/90 (9)
3/49 (6)
2/27 (7)
2/18 (11)
Stable disease (%)
36/213 (17)
16/90 (18)
8/49 (16)
6/27 (22)
4/18 (22)
Progression (%)
48/213 (23)
25/90 (28)
15/49 (31)
5/27 (19)
3/18 (17)
No or Unknown response (%)
56/213 (26)
24/90 (27)
11/49 (22)
8/27 (30)
8/18 (44)
n/N (%): n, number with factor; N, number with valid data for factor.
Figure 1 Figure shows the time to response at any time after time
zero (T0) for the different categories of responses among 213 patients
Figure 2 Figure shows the KaplanMeier curves for event-free
who received at least one treatment after T0.
survival (red curve, median 5 months) and overall survival (blue
curve, median 9 months) from T0 for all patients (n ¼ 286) enrolled on
responses by regimen number (for the first five regimens) in
the study.
Table 3. The median TNT following the first regimen after T0
was 0.5 months. Interestingly, bortezomib and the IMiDs
continued to be used in the subsequent regimens in a significant
proportion of patients. Overall, 75 (35%), 51 (24%) and 63
9 months (95% CI; 7, 11) from T0 (Figure 2). The overall survival
(30%) patients received bortezomib, thalidomide or lenalido-
from diagnosis for the entire cohort was 56 months (95%
mide at some point after T0. The breakdown of the response
CI; 44, 72). The median OS for the 213 patients who received
categories for the newer drug-containing regimen and those
at least one regimen after T0 was 12 months (95% CI; 10,14),
without these three drugs are provided in Supplementary Tables
and for the remaining patients it was 3 months (95% CI; 2,3).
2 and 3. Overall, 94 (44%) of patients had a minimal response
We also examined the OS from T0 based on whether the
or better including a partial response or better in 69 (32%)
patients first met criteria for bortezomib refractoriness or the
patients at some point during the post T0 period. The median
IMiD criteria for inclusion in the study. The median OS from
times to achieving any degree of response are shown in Figure 1.
T0 was 9 months (95% CI; 7,11) for patients meeting
The primary reasons for discontinuing the regimens are detailed
the bortezomib criteria first, similar to 9 months (95% CI;
in Supplementary Table 5 (Supplementary data).
7,13) for patients meeting criteria for IMiDs first (P ¼ 0.44). We
We also examined the frequency of use of high-dose therapy
also separately examined the outcome from the date they
and stem cell transplantation in this population. There were 44
became refractory to bortezomib. The median OS from the
patients who received a transplant after time zero, the median
time they were considered refractory to bortezomib (as
time to transplant was 96 days (B3 months) with the first
defined for the purposes of the study) was 11 months (95%
transplant received after 5 days and the last one received after
CI; 10,14). Similarly, the median OS from the date patients
936 days (B2 years and 5 months). Half of the patients who
were considered to be relapsed/refractory/ineligible to an
received a transplant after T0 received it between 37 days and
IMiD was 22 months (95% CI; 15, 26) for lenalidomide patients
203 days. Among the 44 patients receiving a transplant after T0,
and 16 months (95% CI; 14, 22) for thalidomide patients. We
this was the first transplant in 16 patients (that is, no transplants
further examined the outcome based on whether the patients
were carried out before T0).
received the alternate IMiD. The median OS for lenalidomide
refractory patients receiving thalidomide for salvage was 8
months and for thalidomide refractory patients receiving
Survival outcomes
lenalidomide was 12 months from the start of the second
The median event-free survival for the entire cohort was
IMiD, with the analysis landmarked at the start of the alternate
5 months (95% CI; 4, 6) from T0 and the median OS was
IMiD. The median OS from the time they were refractory to any
Leukemia
Outcome in relapsed myeloma
SK Kumar et al
5
Table 4
Univariate analysis of prognostic factors for OS and EFS from T0
Variable
n/N (%)
OS from time zero
EFS from time zero
HR (95% CI)
P-value
HR (95% CI)
P-value
At Diagnosis
Serum heavy chain: None
27/250 (11)
1.73 (1.03, 2.89)
0.038
1.51 (0.94, 2.42)
0.085
Serum heavy chain: G
155/250 (62)
0.62 (0.45, 0.86)
0.005
0.68 (0.51, 0.91)
0.010
Serum heavy chain: A
60/250 (24)
1.40 (0.98, 2.01)
0.064
1.27 (0.92, 1.76)
0.148
B2MX3.5 mg/l
123/226 (54)
1.59 (1.12, 2.26)
0.009
1.58 (1.15, 2.16)
0.004
Plateleto150 000/ml
50/229 (22)
1.57 (1.06, 2.32)
0.024
1.20 (0.83, 1.72)
0.325
FISH t(4;14)
9/95 (9)
2.14 (0.90, 5.10)
0.086
2.15 (0.97, 4.74)
0.058
Hypodiploidy
14/132 (11)
1.86 (1.01, 3.41)
0.045
1.53 (0.85, 2.77)
0.158
At Time zero
AgeX65 year
115/284 (40)
1.34 (0.98, 1.82)
0.063
1.11 (0.84, 1.46)
0.471
Serum heavy chain: None
23/176 (13)
1.86 (1.10, 3.14)
0.021
1.50 (0.91, 2.46)
0.114
Serum heavy chain: G
108/176 (61)
0.49 (0.33, 0.74)
o0.001
0.58 (0.41, 0.83)
0.002
Serum heavy chain: A
41/176 (23)
1.69 (1.09, 2.61)
0.020
1.54 (1.04, 2.27)
0.029
Albumino3.5 g/dl
152/279 (54)
1.73 (1.26, 2.37)
o0.001
1.47 (1.12, 1.93)
0.006
B2MX3.5 mg/l
108/173 (62)
2.36 (1.55, 3.60)
o0.001
1.71 (1.20, 2.44)
0.003
B2M45.5 mg/l
59/173 (34)
2.20 (1.50, 3.25)
o0.001
1.55 (1.09, 2.21)
0.015
ISS Stage 3
59/172 (34)
2.24 (1.52, 3.31)
o0.001
1.57 (1.10, 2.24)
0.013
Creatinine4ULN
64/185 (35)
2.19 (1.48, 3.25)
o0.001
1.50 (1.06, 2.11)
0.022
FISH t(14;16)
3/38 (8)
5.04 (0.97, 26.16)
0.054
2.43 (0.54, 10.98)
0.250
Time zero cytogenetic abnormalities
23/47 (49)
3.71 (1.43, 9.66)
0.007
1.82 (0.93, 3.55)
0.080
Time zero hypodiploidy
12/47 (26)
3.57 (1.52, 8.38)
0.003
3.77 (1.72, 8.27)
o0.001
At least 1 transplant before time zero
178/286 (62)
1.17 (0.85, 1.61)
0.331
1.29 (0.98, 1.71)
0.072
Abbreviations: CI, confidence interval; EFS, event-free survival; FISH, fluorescence in situ hybridization; HR, hazard ratio; OS, overall survival.
P-value from Wald Chi-square test in cox regression.
one of the novel agent (bortezomib or IMiD) was 10 months
(95% CI: 7,14).
The per regimen outcome of patients on this study is detailed
in Supplementary Table 6, which provides patient disposition
data in terms of treatment status and survival at various time
points from T0. The numbers of patients in each successive
treatment regimen who died during that regimen, received
another treatment, or are still receiving that regimen are shown
in the table.
Prognostic factors
We performed additional analyses to identify prognostic factors
predicting event-free survival and OS following T0. Factors
impacting the OS and event-free survival from T0 identified
in a univariate analysis are shown in Table 4. In a multivariate
Figure 3 Figure shows the overall survival from T0 by ISS stage at T0.
model using stepwise selection that included most of these
variables only B2M45.5 mg/l at T0 (HR: 3.58; P ¼ 0.047) and
albumin o3.5 mg/dl at T0 (HR: 5.62; P ¼ 0.009) were indepen-
dently significant for OS. Given that B2M and serum albumin,
the two components of ISS, was prognostic for survival in this
Discussion
patients group, we examined the outcome based on ISS stage at
T0. As shown in Figure 3, the ISS stage was prognostic for overall
New developments in therapy over the past decade have
survival following T0, with median survivals of 12, 8 and 4
changed the treatment paradigm for myeloma and resulted in
months for ISS stages 1, 2 and 3, respectively. However, the ISS
significant improvement in survival.9,10,12 However, myeloma
stage did not predict event-free survival in this group.
remains incurable and new treatments are currently being
Given that nearly 20% of the patients survive beyond 2 years,
studied. The results of the new drugs, especially those from the
we specifically compared the baseline characteristics of those
single-arm trials, should be interpreted in the context of the
who survived beyond 2 years to those who died within 3 months
expected outcomes in this group of patients. However, the rapid
of reaching T0. The results of the comparison, which is detailed
pace of development in the area of myeloma therapy has
in Supplementary Table 7, demonstrated significant differences
precluded a good understanding of the outcome among patients
between the two groups in terms of lower B2M and fewer
who have exhausted the currently available therapies. The
patients with ISS stage 3 both at diagnosis and at T0, normal
natural history of relapsed myeloma has been studied pre-
creatinine at T0, and at least a partial response or better before
viously, but before the new drugs became available. Specifi-
T0 among the group with longer survival.
cally, one study included 578 patients with newly diagnosed
Leukemia
Outcome in relapsed myeloma
SK Kumar et al
6
MM who were followed up and monitored throughout their
stopped responding to it, with variable degrees of responses.22
clinical course at a single institution between 1985 and 1998.13
Bortezomib has activity with retreatment 2225 and lenalidomide
The OS for the 578 patients at 1, 2 and 5 years was 72%, 55%,
has significant activity in thalidomide refractory population.6 As
and 22%, respectively; the median OS from initial therapy was
in this study, many of the current clinical trials include a similar
28.4 months. The median OS of 355 patients who had relapsed
mix of patients and the response rates seen in these phase 2 trials
at the time of the analysis was 17.1 months from initiation of the
and in phase 3 trials utilizing standard of care for the control arm
second therapy, and 84% died within 5 years. This study
should be considered in the context of these findings. In contrast
revealed decreasing response duration with increasing number
to previous studies, we do not see a progressive decline in
of salvage regimens, likely reflecting acquired drug resistance.
response rates and duration of response.13 This may be a
The median survival of patients who had three previous
reflection of increasing treatment choices that are available
therapies in the initial trials of bortezomib for similar patients
compared with a decade ago when alkylating agents and
was 12 months compared with the 5 months seen in that study
steroids formed the basis of myeloma treatment.26 Also, some
demonstrating clinically relevant activity for the drug.14
degree of selection bias leading to patients with better
Similarly, the overall survival of heavily pre-treated patients in
performance status, as well as patients with more indolent
the initial study of thalidomide demonstrated a 58% overall
disease being considered for multiple therapies cannot be
survival at 12 months, again demonstrating improvement over
excluded.
historical data.15 However, with the improved survival due to
Despite the initial responses of over 30% in this group of
the widespread use of IMiDs and bortezomib these data are no
relapsed and refractory patients, the median event-free survival
longer reflective of the current practice.
of 5 months and OS of 9 months highlight the limited durability
It is important to understand the clinical course of patients,
of these responses and the poor overall outcome among patients
who have become refractory to one or more of these agents and
who are no longer responding to the existing newer therapies.
hence our study was focused on patients considered refractory
This is consistent with recent reports showing the poor outcome
to bortezomib and at least one of the IMiDs. However, these
of patients refractory to IMiDs even in the context of stem cell
drug scan be used in combination with a variety of agents,
transplantation.27 Another important finding from the study was
giving rise to multitude of regimens and detailed information
the continued value of conventional prognostic factors in this
regarding the specific combinations these drugs were part of is
patient group. Interestingly, the ISS staging parameters B2M
not available. In the current study, we specifically enrolled
and serum albumin at T0 best predicted survival outcome in this
patients who would be considered eligible for a clinical trial, by
group of patients and should be taken into account when
restricting to patients with good performance status and those
comparing results between different trials. They could in fact be
with measurable disease at the point at which they would be
incorporated as stratification factors in clinical trials of new
considered refractory to bortezomib and to one of the IMiDs.
drugs.28 Unfortunately, limited data were available with respect
The definitions for refractory disease were based on the
to cytogenetic and fluorescence in situ hybridization features in
recommendations of the ASH/FDA Panel on clinical endpoints
the current study. However, examination of the available data
in myeloma.16 Patients eligible for clinical trials generally have
suggests retained prognostic value for these characteristics.
better survival outcomes irrespective of diseases being
Patients with high-risk genetic abnormalities such as t(4;14),
studied17,18 which does limit the generalizability of the results
t(14;16) and hypodiploidy had shorter duration of responses and
to the myeloma patient population as a whole; but at the same
poorer OS compared with the other patients.2931 As has been
time allows better comparison with the current clinical trials.
seen in previous studies in the context of newly diagnosed
We also only required failure of either one of the IMiDs to be
disease, the presence of renal insufficiency predicted poorer
eligible for the study, taking into account the varied availability/
survival. This might to some extent reflect the lack of enrollment
accessibility of the two drugs in different parts of the world. By
in clinical trials of patients with compromised renal function.
incorporating patients from several large centers from different
Clearly the results presented here have some drawbacks,
geographical regions, similar to what is often seen in the large
particularly the inability to study patients who are refractory to
multicenter trials, we hoped to overcome the effect of
individual IMiDs, the prognostic value of all genetic risk factors
heterogeneity of clinical practice. By using a uniform approach,
in the context of specific therapies and the variations across
we have therefore sought to minimize the heterogeneity
different geographical areas based on clinical practices and drug
in reporting that can happen in a multicenter study.19,20
availability. An ongoing study is recruiting additional patients to
One of the most striking findings in our study has been the
extend the current analyses.
response rates seen in this patient population with the first
In conclusion, the current study provides valuable insights
regimen used after they become refractory to the new drugs. The
into the natural history of myeloma after it become non-
overall response seen in a third of the patients can be due to
responsive to the novel therapies. Clearly there are some
several factors. With the advent of the new drugs, older drugs
disadvantages with the current study, such as the inclusion of
such as alkylators are increasingly being relegated to later stages
only `trial eligible' patients and the lack of uniform availability
of disease. It has been shown in the setting of transplant, that
of modern prognostic factors such as cytogenetic and fluores-
patients relapsing after IMiD therapy can obtain comparable
cence in situ hybridization abnormalities. However, the results
response duration with delayed transplant as with early
provide an important reference point for comparison of the
transplant suggesting preservation of sensitivity of tumor cells
results of the ongoing phase 2 and possibly phase 3 trials of new
to alkylators.21 In fact, alkylators were the most common drugs
drugs in myeloma.
used for treatment of patients once they stopped responding to
the newer drugs in the current study. In addition, transplant is
increasingly being used later in the disease course, as is second
Conflicts of interest
transplants as salvage therapy. In fact in the current study nearly
20% of patients received a transplant after T0, a third of which
JJL is on the Scientific advisory boards of Celgene and Janssen-
were first time transplants. Finally, many of the new drugs can
Cilag. PGR and JSM are Advisory board participants for Celgene,
be used again in patients who initially responded but had
Millenium, Johnson and Johnson. DS is on the Speakers Bureau
Leukemia
Outcome in relapsed myeloma
SK Kumar et al
7
and BD is an Advisory board participant for Celgene and
14 Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S,
Millenium. AP is an Advisory Board participant for Celgene,
Irwin D et al. A phase 2 study of bortezomib in relapsed, refractory
Johnson and Johnson. JB has received Honoraria for lectures and
myeloma. N Engl J Med 2003; 348: 26092617.
advisory boards from Celgene, Jansen Cilag and Grant support
15 Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P
et al. Antitumor activity of thalidomide in refractory multiple
from Celgene and Jansen-Cilag. The remaining authors declare
myeloma. N Engl J Med 1999; 341: 15651571.
no conflict of interest.
16 Anderson KC, Kyle RA, Rajkumar SV, Stewart AK, Weber D,
Richardson P. Clinically relevant end points and new drug
approvals for myeloma. Leukemia 2008; 22: 231239.
Author's contributions
17 Davis S, Wright PW, Schulman SF, Hill LD, Pinkham RD,
Johnson LP et al. Participants in prospective, randomized clinical
All authors (except JC, JH, JF and AH) provided patient data and
trials for resected non-small cell lung cancer have improved
survival compared with nonparticipants in such trials. Cancer
were involved in manuscript preparation. JC, JH, JF and AH
1985; 56: 17101718.
were involved in the statistical analysis.
18 Karjalainen S, Palva I. Do treatment protocols improve end results?
A study of survival of patients with multiple myeloma in Finland.
BMJ 1989; 299: 10691072.
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8
Appendix
Go¨sta Gahrton, Karolinska Institute for Medicine, Huddinge,
Sweden
International Myeloma Working Group
Ramo´n Garci´a-Sanz, University Hospital of Salamanca,
Niels Abildgaard, Syddansk Universitet, Odense, Denmark
Salamanca, Spain
Rafat Abonour, Indiana University School of Medicine,
Christina Gasparetto, Duke University Medical Center,
Indianapolis, Indiana, USA
Durham, North Carolina, USA
Ray Alexanian, MD Anderson, Houston, Texas, USA
Morie Gertz, Mayo Clinic, Rochester, Minnesota, USA
Melissa Alsina, H. Lee Moffitt Cancer Center and Research
John Gibson, Royal Prince Alfred Hospital, Sydney, Australia
Institute, Tampa, Florida, USA
Sergio Giralt, MD Anderson Cancer Center, Houston, Texas,
Kenneth C. Anderson, DFCI, Boston, Massachusetts, USA
USA
Michael Attal, Purpan Hospital, Toulouse, France
Hartmut Goldschmidt, University Hospital Heidelberg, Hei-
Herve´ Avet-Loiseau, Institute de Biologie, Nantes, France
delberg, Germany
Ashraf Badros, University of Maryland, Baltimore, Maryland,
Philip Greipp, Mayo Clinic, Rochester, Minnesota, USA
USA
Roman Hajek, Brno University, Brno, Czech Republic
Dalsu Baris, National Cancer Institute, Bethesda, Maryland,
Izhar Hardan, Tel Aviv University, Tel Aviv, Israel
USA
Parameswaran Hari, Medical College of Wisconsin, Milwau-
Bart Barlogie, M.I.R.T. UAMS Little Rock, Arkanas, USA
kee, Wisconsin, USA
Re´gis Bataille, Institute de Biologie, Nantes, France
Jean-Luc Harousseau, Institute de Biologie, Nantes, France
Meral Beksac¸, Ankara University, Ankara, Turkey
Hiroyuki Hata, Kumamoto University Hospital, Kumamoto,
Andrew Belch, Cross Cancer Institute, Alberta, Canada
Japan
Dina Ben-Yehuda, Hadassah University Hospital, Hadassah,
Yutaka Hattori, Keio University School of Medicine, Tokyo,
Israel
Japan
Bill Bensinger, Fred Hutchinson Cancer Center, Seattle,
Tom Heffner, Emory University, Atlanta, Georgia, USA
Washington, USA
Joy Ho, Royal Prince Alfred Hospital, Sydney, Australia
P. Leif Bergsagel, Mayo Clinic Scottsdale, Scottsdale, Arizona, USA
Vania Hungria, Clinica San Germano, Sao Paolo, Brazil
Jenny Bird, Bristol Haematology and Oncology Center,
Shinsuke Ida, Nagoya City University Medical School,
Bristol, UK
Nagoya, Japan
Joan Blade´, Hospital Clinica, Barcelona, Spain
Peter Jacobs, Constantiaberg Medi-Clinic, Plumstead, South
Mario Boccadoro, University of Torino, Torino, Italy
Africa
Michele Cavo, Universita di Bologna, Bologna, Italy
Sundar Jagannath, Mt. Sinai Cancer Institute, New York, New
Asher Chanan-Khan, Roswell Park Cancer Institute, Buffalo,
York, USA
New York USA
Hans Johnsen, AHSIC Aarhus University, Aalbor, Denmark
Wen Ming Chen, MM Research Center of Beijing, Beijing,
Hou Jian, Shanghai Chang Zheng Hospital, Shanghai, China
China
Douglas Joshua, Royal Prince Alfred Hospital, Sydney,
Tony Child, Leeds General Hospital, Leeds, United Kingdom
Australia
James Chim, Department of Medicine, Queen Mary Hospital,
Artur Jurczyszyn, The Myeloma Treatment Foundation,
Hong Kong
Poland
Wee-Joo Chng, National University Health System, Singapore
Michio Kawano, Yamaguchi University, Ube, Japan
Ray Comenzo, Tufts Medical School, Boston, Massachusetts,
Nicolaus Kro¨ger, University Hospital Hamburg, Hamburg,
USA
Germany
John Crowley, Cancer Research and Biostatistics, Seattle,
Shaji Kumar, Department of Hematology, Mayo Clinic,
Washington, USA
Minnesota, USA
William Dalton, H. Lee Moffitt, Tampa, Florida, USA
Robert A. Kyle, Department of Laboratory Med. and
Faith Davies, Royal Marsden Hospital, London, England
Pathology, Mayo Clinic, Minnesota, USA
Ca´rmino de Souza, Univeridade de Campinas, Caminas,
Martha Lacy, Mayo Clinic Rochester, Rochester, Minnesota,
Brazil
USA
Michel Delforge, University Hospital Gasthuisberg, Leuven,
Juan Jose´ Lahuerta, Grupo Espan~ol di Mieloma, Hospital
Belgium
Universitario 12 de Octubre, Madrid, Spain
Meletios Dimopoulos, University of Athens School of
Ola Landgren, National Cancer Institute, Bethesda, Maryland,
Medicine, Athens, Greece
USA
Angela Dispenzieri, Mayo Clinic, Rochester, Minnesota, USA
Jacob Laubach, Dana-Farber Cancer Institute, Boston, Mas-
Johannes Drach, University of Vienna, Vienna, Austria
sachusetts, USA
Matthew
Drake,
Mayo
Clinic
Rochester,
Rochester,
Jae Hoon Lee, Gachon University Gil Hospital, Incheon,
Minnesota, USA
Korea
Brian G.M. Durie, Cedars-Sinai Samuel Oschin Cancer
Xavier LeLeu, Hospital Huriez, CHRU Lille, France
Center, Los Angeles, California, USA
Suzanne Lentzsch, University of Pittsburgh, Pittsburgh,
Hermann Einsele, Universita¨tsklinik Wu¨rzburg, Wu¨rzburg,
Pennsylvania, USA
Germany
Henk Lokhorst, University Medical CenterUtrecht, Utrecht,
Theirry Facon, Centre Hospitalier Regional Universitaire de
The Netherlands
Lille, Lille, France
Sagar Lonial, Emory University Medical School, Atlanta,
Dorotea Fantl, Socieded Argentinade Hematolgia, Buenos
Georgia, USA
Aires, Argentina
Heinz Ludwig, Wilhelminenspital Der Stat Wien, Vienna,
Jean-Paul Fermand, Hopitaux de Paris, Paris, France
Austria
Rafael Fonseca, Mayo Clinic Arizona, Scottsdale, Arizona,
Angelo Maiolino, Rua fonte da Saudade, Rio de Janeiro,
USA
Brazil
Leukemia
Outcome in relapsed myeloma
SK Kumar et al
9
Mari´a Mateos, University of Salamanca, Salamanca, Spain
Kazuyuki Shimizu, Nagoya City Midori General Hospital,
Jayesh Mehta, Northwestern University, Chicago, Illinois, USA
Nagoya, Japan
Ulf-Henrik
Mellqvist,
Sahlgrenska
University
Hospital,
Chaim Shustik, McGill University, Montreal, Canada
Gothenburg, Sweden
David Siegel, Hackensack, Cancer Center, Hackensack, New
GiamPaolo Merlini, University of Pavia, Pavia, Italy
Jersey, USA
Joseph Mikhael, Mayo Clinic Arizona, Scottsdale, Arizona,
Seema Singhal, Northwestern University, Chicago, Illinois,
USA
USA
Angelina Rodri´guez Morales, Bonco Metro Politano de
Pieter Sonneveld, Erasmus MC, Rotterdam, The Netherlands
Sangre, Caracas, Venezuela
Andrew Spencer, The Alfred Hospital, Melbourne, Australia
Philippe Moreau, University Hospital, Nantes, France
Edward Stadtmauer, University of Pennsylvania, Philadelphia,
Gareth Morgan, Royal Marsden Hospital, London, England
Pennsylvania, USA
Hareth Nari, Karolinska University Hospital, Stockholm,
Keith Stewart, Mayo Clinic Arizona, Scottsdale, Arizona, USA
Sweden
Evangelos Terpos, University of Athens School of Medicine,
Nikhil Munshi, Diane Farber Cancer Institute, Boston,
Athens, Greece
Massachusetts, USA
Patrizia Tosi, Italian Cooperative Group, Istituto di Ematologia
Ruben Niesvizky, Weill Medical College of Cornell Uni-
Seragnoli, Bologna, Italy
versity, New York, New York, USA
Guido Tricot, Huntsman Cancer Institute, Salt Lake City,
Amara Nouel, Hospital Rutz y Paez, Bolivar, Venezuela
Utah, USA
Yana Novis, Hospital Si´rioLibane^s, Bela Vista, Brazil
Ingemar Turesson, SKANE University Hospital, Malmo,
Robert Orlowski, MD Anderson Cancer Center, Houston,
Sweden
Texas, USA
Ben Van Camp, Vrije Universiteit Brussels, Brussels, Belgium
Antonio Palumbo, Cathedra Ematologia, Torino, Italy
Brian Van Ness, University of Minnesota, Minneapolis,
Santiago Pavlovsky, Fundaleu, Buenos Aires, Argentina
Minnesota, USA
Linda Pilarski, University of Alberta, Alberta, Canada
Ivan Van Riet, Brussels Vrija University, Brussels, Belgium
Raymond Powles, Leukemia & Myeloma, Wimbledon,
Isabelle Vande Broek, Vrije Universiteit Brussels, Brussels,
England
Belgium
Noopur Raje, Massachusetts General Hospital, Boston,
Karin Vanderkerken, Vrije University Brussels VUB, Brussels,
Massachusetts, USA
Belgium
S. Vincent Rajkumar, Mayo Clinic,Rochester,Minnesota,USA
Robert Vescio, Cedars-Sinai Cancer Center, Los Angeles,
Donna Reece, Princess Margaret Hospital, Toronto, Canada
California, USA
Tony Reiman, Cross Cancer Institute, Alberta, Canada
David Vesole, Hackensack Cancer Center, Hackensack, New
Paul G. Richardson, Dana Farber Cancer Institute, Boston,
Jersey, USA
Massachusetts, USA
Anders Waage, University Hospital, Trondheim, Norway
David Roodman, University of Pittsburgh School of Medicine,
NSMG
Pittsburgh, Pennsylvania USA
Michael Wang, MD Anderson, Houston, Texas, USA
Laura Rosin~ol, Hospital Clinic, Barcelona, Spain
Donna Weber, MD Anderson, Houston, Texas, USA
Jesu´s San Miguel, University of Salamanca, Salamanca, Spain
Jan Westin, Sahlgrenska University Hospital, Gothenburg,
Orhan Sezer, Universita¨t Hamburg, Hamburg, Germany
Sweden
Jatin J. Shah, MD Anderson Cancer Institute, Houston, Texas,
Keith Wheatley, University of Birmingham, Birmingham,
USA
United Kingdom
John Shaughnessy, M.I.R.T. UAMS, Little Rock, Arkansas,
Jeffrey Zonder, Karmanos Cancer Institute, Detroit, Michigan,
USA
USA
Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
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