Stem Cell Transplant in Multiple Myeloma:
Impact of Response Failure in the Era of Novel Therapies
Morie A. Gertz, MD; Shaji Kumar, MD; Martha Q. Lacy, MD; Angela Dispenzieri, MD; David Dingli, MD, PhD; Suzanne R. Hayman, MD; Francis K. Buadi, MD; William J. Hogan, MB, BCh
Division of Hematology, Mayo Clinic, Rochester, Minnesota
Introduction
Results
Table 1. Characteristics of Patientsa
Table 2. Baseline Differences by Group
Figure 1
Figure 2
Discussion
Characteristic
Valueb
Pretransplant
Plateau Refractory Relapse off Relapse on
Relapsed-
P Value
Some experts have suggested that induction treatment
The study population consisted of 324 patients
Male sex
183 (56)
Variablea
Therapy
Therapy
Refractory
Previously, the administration of high-dose therapy
may not be required at all if high-dose therapy is
(Table 1). The patients who were not in a plateau
Dates
November 1999-November
Serum M-protein spike, g/dL
0.4
1.8
1.9
0.9
1.5
.001
was performed whether or not a response to
planned, since the clinical impact of pretransplant
at the time of transplant had a significantly greater
Myeloma diagnosis
2008
Plasma cells, %
5
23
20
23
22
<.001
induction therapy occurred, with no compromise
cytoreduction was minimal. It was also possible to
serum
SCT
May 2000-February 2009
2-microglobulin value (2.9 vs 2.2 mg/L),
2-Microglobulin, mg/L
2.24
3.30
2.72
2.90
2.90
<.001
in PFS or overall survival. However, none of these
collect stem cells successfully without pretransplant
labeling index (1% vs 0), and percentage of bone
Age, median (10-90 percentile), y
59 (46-68)
Abnormal cytogenetics at SCT,
11
20
38
35
30
.001
patients received a novel agent.
cytoreduction. However, all these data are from
marrow plasma cells (22% vs 5%) at transplant
Serum M protein
%
The role of stem cell transplant for patients
the era before the introduction of novel agents.
(Table 2), as would be expected because of the
Ak
47 (15)
Labeling index
0
0.7
1.3
0.8
1.0
<.001
A
18 (6)
who never achieve PR or have disease relapse
Induction therapies were primarily corticosteroid
lack of response to induction treatment. Most
Age, y
58.8
58.0
60.6
61.8
60.2
.42
Gk
11 (34)
immediately before high-dose therapy is not well
based, such as doxorubicin, dexamethasone, and
patients responded to induction treatment, and a
Creatinine, mol/L
80
88
80
80
88
.60
G
75 (23)
defined in the era of novel agents. The median
vincristine; doxorubicin-methylprednisolone; or
pretreatment PR was present in 247 (76%). Patients
Freek
24 (7)
Period from diagnosis to stem
6.1
6.0
9.5
10.3
7.2
<.001
cell transplant, mo
time to progression was 13.1 months (Figure 2), in
the combination of cyclophosphamide, vincristine,
considered primary refractory numbered 30 (9%);
Free
22 (7)
novel agent induction failures. Patients who have
doxorubicin, and methylprednisolone. At that time,
relapse on therapy, 26 (8%); and relapse off therapy,
M
3 (1)
Abbreviation: SCT, stem cell transplant.
induction failures to novel agents appear to have
response rates before transplant hovered in the 50%
21 (6%). The 3 groups of nonresponders were
D
3 (1)
a Aggregates relapse on therapy, relapse off therapy, and primary refractory into a single group.
Biclonal
2 (1)
inherent biologic characteristics that lead to a more
range, with few complete responses. Currently, 30%
combined into a single category of relapsed-refractory
None
101 (31)
rapid regrowth of the myeloma cell population
to 60% of patients commonly have a very good partial
to improve the statistical power of comparisons
Urine
Failure to respond to novel-agent induction leads to shorter posttransplant
Failure to respond to novel-agent induction leads to shorter posttransplant
after high-dose melphalan therapy.
remission (VGPR) or better after 4 cycles of induction
between baseline characteristics at transplant
k
170 (52)
progression-free survival (PFS). PFS from day 0 of transplant, based on response
progression-free survival (PFS). PFS from day 0 of transplant, based on response
with novel-agent therapy. The purpose of this study
and PFS after transplant. There are significantly
101 (31)
Table 3. Posttransplant Responses
status at transplant. Medians are 22.6, 15.3, 13.8, and 12.0 months for plateau
status at transplant and comparing plateau with refractory and relapsing combined.
(n=247), refractory (n=30), relapse off therapy (n=21), and relapse on therapy (n=26),
Medians are 22.6 months for plateau (n=247) and 13.1 months for refractory or
was to report the outcomes of patients after high-
higher CR and VGPR rates for patients who
Anuric
5 (2)
respectively (P<.001).
relapsing (n=77) (P<.001).
dose therapy, stratified in accordance with whether a
before transplant were in the plateau group (53%)
None
48 (15)
Plateau
Refractory Relapse off Therapy
Relapse on Therapy
Relapsed-
patient achieved PR or better after novel agentbased
compared with patients in all other groups (30%)
Abnormal cytogenetics at SCT (n=321)
49 (15)
Variablea
(n=247)
(n=30)
(n=26)
(n=21)
Refractoryc
induction therapy.
(P<.001). (Table 3)
Myeloma bone disease apparent on plain radiographs, yes/no
280 (86)/44 (14)
CR
98 (40)b
3 (10)
4 (15)
5 (24)
12 (16)
Conclusion
Prior radiation therapy, yes/no
88 (27)/236 (73)
VGPR
31 (13)b
3 (10)
4 (15)
4 (19)
11 (14)
Creatinine, median (10-90 percentile), mol/L
80 (62-124)
PR
109 (44)
15 (50)
16 (62)
10 (48)
41 (53)
Figure 3
Figure 4
Survival
Conditioning
<PR
9 (4)
9 (30)
2 (8)
2 (10)
13 (17)
This retrospective study analyzes progression-free
At the time of our analysis, 44% of patients in the
MEL200
279 (86)
survival and overall survival in patients who do
Abbreviations: CR, complete remission; PR, partial response; VGPR, very good partial remission.
Materials and Methods
relapsed-refractory group had died, compared
MEL<200
27 (8)
not have a partial response after induction therapy
a Values are expressed as number and percentage of patients.
with 23% in the plateau group. Also, the multiple
MEL + Y90 anti-CD20
6 (2)
b CR+VGPR for plateau, P<.001 compared with other 3 categories.
with a regimen that contains a novel agent. Unlike
c
myeloma of 81% of the relapsed-refractory group
Samarium + MEL200
12 (4)
Aggregates relapse on therapy, relapse off therapy, and primary refractory into a single
patients in reports published previously--before
Patients could have received no more than 1 prior
had progressed, compared with 53% of the plateau
Period from diagnosis to SCT, median (10-90 percentile), mo
6.3 (4.5-12.0)
novel agents--patients who do not achieve partial
Stem cell mobilization, chemotherapy, and growth factor/ TABLE: Changes
98 (30)/226
of
(70)
GS from the initial biopsy to
therapy, and treatment induction must have contained
group. Figure 1 gives the PFS of all 4 groups. .
remission have a significantly shorter overall
growth factor only
thalidomide, lenalidomide, or bortezomib. Patients
the follow-up biopsy
Figure 2 shows the PFS from stem cell transplant
survival from transplant (74.0 vs 43.5 months)
Disease status at SCT
were grouped into 4 categories. The first category
collapsing the 3 nonplateau groups
and a shorter progression-free survival (22.6 vs
Plateau
247 (76)
Table 4.
contained patients with a disease response (ie, 50%
Multivariable Analysis of Posttransplant Progression-Free Survival
13.1 months; P<.001). Absence of a response to
A statistically significant difference was seen in
Never achieved PR (refractory)
30 (9)
decrease in M-protein level) to initial induction
induction therapy with a novel agent predicts a
overall survival when all 4 groups were compared
Relapse off therapy
21 (6)
P Value
therapy. This category was labeled plateau. The second
Relapse on therapy
26 (8)
poorer outcome after high-dose therapy.
(Figure 3). A significant difference in survival was
Variable
category contained patients who did not have at least
3.4 (1.6-4.4)
Plateau vs relapsed-refractory
.003
seen when all patients with refractory and relapsing
2-Microglobulin at initial diagnosis, median (10-90 percentile),
a PR (ie, <50% or a greater decrease in M-protein
mg/L (n=235)
Albumin
.86
disease were combined into a single group (Figure
level with induction therapy); for these patients, the
Labeling index, median (10-90 percentile) (n=320)
0.2 (0-2.0)
Sex
.94
4). When survival was compared among those
therapy was considered an initial failure and this
Induction therapy administered (N=324)
patients achieving VGPR or better posttransplant,
2-Microglobulin
.89
Thalidomide dexamethasone
198 (61)
category was labeled refractory. The third category
Bone marrow plasma cells
.18
there was no survival advantage of a pretransplant
Lenalidomide dexamethasone
198 (61)
Failure to respond to novel-agent induction leads to shorter posttransplant
Failure to respond to novel-agent induction leads to shorter posttransplant overall
was composed of patients who had a disease response
Age
.75
overall survival. Overall survival from day 0 of transplant, based on response
survival. Overall survival from day 0 of transplant, based on response status at
response to novel agents (75% vs 70% at 48 months;
Lenalidomide dexamethasone
108 (33)
status at transplant. Medians are 73.9, 39.5, 68.9, and 23.8 months for plateau
transplant and comparison with plateau with refractory or relapsing combined.
with more than a 50% reduction in M component and
Abnormal cytogenetics
.002
P=.67).
Bortezomib dexamethasone
8 (2)
CTX mobilization
.51
(n=247), refractory (n=30), relapse off therapy (n=21), and relapse on therapy (n=26),
Medians are 73.9 months for plateau (n=247) and 43.5 months for refractory or
then had a relapse, defined as a rise of M protein by
Combinations of novel agents
10 (3)
respectively (P=.007).
relapsing (n=77) (P<.001). BMT indicates bone marrow transplant.
Labeling index
.002
25% during the continuation of induction therapy.
A multivariable analysis was performed of risk
Abbreviations: MEL, melphalan; MEL200, high-dose melphalan (200 mg/m2); MEL<200, low-dose melphalan (<200
They were classified into 2 subgroups depending
factors for PFS (Table 4). The patient status at
mg/m2); PR, partial response; SCT, stem cell transplant.
Abbreviation: CTX, cyclophosphamide.
a N=324.
on whether disease progression occurred after a
transplant--plateau versus relapsed-refractory--
b Categorical data are expressed as number and percentage of patients.
response during induction therapy (relapse on therapy)
was significant for PFS (P=.003; hazard ratio, 1.72),
or whether progression occurred after induction
as were the labeling index (P<.002; hazard ratio,
therapy was discontinued but before day 0 of stem
1.21) and cytogenetics (P<.002; hazard ratio, 2.0).
cell transplant (relapse off therapy).
© 2009 Mayo Foundation for Medical Education and Research