Article
Early versus Late Discontinuation of Maintenance Therapy in
Multiple Myeloma
Jordan Nunnelee 1,2, Francesca Cottini 3, Qiuhong Zhao 3, Muhammad Salman Faisal 3,4, Patrick Elder 3,
Ashley Rosko 3, Naresh Bumma 3, Abdullah Khan 3, Elvira Umyarova 3, Srinivas Devarakonda 3, Don M. Benson 3,
Yvonne A. Efebera 3,5 and Nidhi Sharma 3,*
College of Medicine, The Ohio State University, Columbus, OH 43210, USA
Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
3 Department of Internal Medicine, Division of Hematology, The Ohio State University,
Columbus, OH 43210, USA
4 Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
5 Bone Marrow Transplantation & Cellular Therapy, OhioHealth, Columbus, OH 43210, USA
* Correspondence: nidhi.sharma@osumc.edu
1
2
Citation: Nunnelee, J.; Cottini, F.;
Zhao, Q.; Faisal, M.S.; Elder, P.;
Rosko, A.; Bumma, N.; Khan, A.;
Umyarova, E.; Devarakonda, S.; et
al. Early versus Late Discontinuation
of Maintenance Therapy in Multiple
Myeloma. J. Clin. Med. 2022, 11, 5794.
https://doi.org/10.3390/jcm11195794
Abstract: Maintenance therapy after autologous stem cell transplant (ASCT) in multiple myeloma
(MM) is the standard treatment and recommended to be continued until disease progression. How‐
ever, in the real world, patients discontinue treatment due to various reasons. We sought to deter‐
mine the effect of early versus late discontinuation on survival outcomes in MM patients who un‐
derwent ASCT at The Ohio State University. We retrospectively reviewed 340 patients who under‐
went ASCT from 2005 to 2016 and received maintenance therapy for at least six months without
progression. We compared the outcomes of patients who received maintenance for three years or
less (early group) to the patients who continued maintenance beyond three years (late group). Le‐
nalidomide (89%) and bortezomib (10%) were the most common agents used for maintenance chem‐
otherapy. In Kaplan–Meier analysis, patients in the late group had prolonged progression‐free (PFS)
(p < 0.001) and overall survival (OS) (p < 0.001). The 5‐year estimated OS in late group was 96% vs.
79% in the early group and 5‐year PFS was 80% in late group vs. 50% in the early group. The most
common reasons for discontinuation of maintenance in early group were adverse events (55.9%)
and patient preference (22.5%). For the late group, it was disease progression (23.9%) and adverse
events (14.3%). Fifty‐five percent of patients in the late group were still on maintenance treatment
at the last follow‐up. Continuation of maintenance therapy was thus associated with improved out‐
comes, while adverse events prevented most patients from continuing treatment.
Academic Editor: Francesca Patriarca
Keywords: multiple myeloma; maintenance; adverse events; lenalidomide
Received: 8 September 2022
Accepted: 27 September 2022
Published: 29 September 2022
Publisher’s Note: MDPI stays neu‐
1. Introduction
tral with regard to jurisdictional
High‐dose chemotherapy, followed by autologous stem cell transplant (ASCT), is the
mainstay of treating multiple myeloma (MM) [1,2]. Despite our advances in MM treat‐
ment, almost all the patients who receive autologous transplant relapse at some point
[3,4]. Over the last two decades, clinicians have tried different strategies to delay and de‐
crease the risk of relapse. A concept of “total therapy” pioneered planned tandem trans‐
plant and maintenance therapy with alpha interferon in the late 1990s at the University of
Arkansas Medical Center [5]. This showed an increased rate of complete remission and
improvement of progression‐free survival (PFS) and overall survival (OS). In a subse‐
quent clinical trial, in comparison with single transplant, tandem transplant showed dou‐
bling of OS at seven years after tandem transplant (21% vs. 42%, p = 0.01). The survival
benefit of double transplant was most significant for patients who did not achieve very
good partial remission after the first transplant (11% for single transplant vs. 43% for
claims in published maps and institu‐
tional affiliations.
Copyright: © 2022 by the authors. Li‐
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con‐
ditions of the Creative Commons At‐
tribution (CC BY) license (https://cre‐
ativecommons.org/licenses/by/4.0/).
J. Clin. Med. 2022, 11, 5794. https://doi.org/10.3390/jcm11195794
www.mdpi.com/journal/jcm
J. Clin. Med. 2022, 11, 5794
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double transplant, p < 0.001) [6]. However, with the arrival of newer chemotherapy agents,
the tandem transplant did not show benefit in a larger clinical trial (BMT CTN 0702) and
fell out of favor [7,8]. Similarly, post‐transplant consolidation showed benefit with im‐
proved depth of response and prolongation of PFS and OS in clinical trials. However, its
use has been limited due to side effects in post‐transplant [9,10]. A large multicenter pro‐
spective clinical trial (BMT CTN 0702) compared three arms; ASCT, tandem transplant,
and autologous transplant followed by consolidation therapy. All patients got mainte‐
nance with lenalidomide after transplant. The 3‐year PFS was 54%, 58%, and 58%, while
OS was 82%, 85%, and 84%, respectively, without any significant difference, thus estab‐
lishing non‐superiority of consolidation compared to tandem transplant [7].
The initial reports of maintenance therapy use after transplant came in the 1990s.
Steroids and interferons were among the initial agents used. Unfortunately, these agents’
long‐term use came with adverse effects limiting their use [11–14]. Thalidomide was the
first novel agent added to maintenance regimens with mixed success [15–18]. Meta‐anal‐
ysis of thalidomide use in maintenance therapy showed improvement in PFS and OS [19].
However, the use in the clinical setting remained limited due to the significant side effect
of peripheral neuropathy and was associated with a high risk of discontinuation of ther‐
apy and decreased quality of life [20].
Lenalidomide is a newer immunomodulatory agent with better tolerability and safety
profile. It has been studied in multiple clinical trials for maintenance therapy after ASCT
and has shown PFS and OS benefit [21,22]. Bortezomib, a proteasome inhibitor, has also
been studied as a maintenance agent in the HOVON‐65/GMMG‐HD4 trial [23]. The current
recommendation of the American Society for Blood and Marrow Transplantation is mainte‐
nance therapy with an immunomodulatory drug such as lenalidomide if there is no contra‐
indication, or bortezomib in patients with high‐risk cytogenetics or renal failure [24].
Ideally, maintenance therapy is continued until disease progression. However, this
is not always the case. For example, in the IFM‐05 trial, 27% of patients discontinued
maintenance due to adverse events [25]. Similarly, bortezomib maintenance in HOVON
65/GMMG‐HD4 was stopped prematurely in 11% of cases due to side effects and 36% of
cases due to disease progression [23]. In the IFM study of lenalidomide maintenance ver‐
sus placebo after ASCT, maintenance was stopped early after 1–2 years due to a higher
risk of second primary malignancy (SPM) in the maintenance arm [25].
In this study, we sought to analyze the effect of early (defined as discontinuation of
maintenance therapy before three years of starting maintenance) versus late (>3 years of
maintenance therapy) discontinuation of maintenance therapy on survival outcomes.
2. Methods
2.1. Study Design and Patients
We retrospectively analyzed data collected from 340 patients diagnosed with multi‐
ple myeloma, who received their first ASCT at The Ohio State University James Cancer
Center from 2005 to 2016. The patients started maintenance therapy approximately 100
days from ASCT. Maintenance therapy was defined as treatment post‐ASCT without the
evidence of progressive disease based on IMWG criteria. We only included patients who
received maintenance therapy for at least six months. The patients were grouped based
on the duration of maintenance therapy: three years or less (early discontinuation group
or early group), and more than three years (late group or continuation group). In the early
group, we excluded the patients who discontinued maintenance therapy due to progres‐
sion of the disease.
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2.2. Endpoints
The primary endpoints included PFS and OS. Progression was defined per IMWG cri‐
teria. All the endpoints were measured from the time of ASCT. This study’s secondary ob‐
jective was to determine the reasons for discontinuing maintenance treatment in both
groups. Discontinuation was defined as permanently stopping the maintenance medication.
If the medication was kept on hold and restarted at any point before disease progression, it
was grouped as being on maintenance therapy. In the case of a change of agent without
disease progression, the patient was still grouped as being on maintenance therapy.
2.3. Statistical Analysis
Patient, disease, and transplant‐related characteristics were compared between the
two groups using the Mann–Whitney U test for continuous variables, and chi‐squared or
Fisher’s exact test for categorical variables. The probabilities of OS and PFS were calcu‐
lated using the Kaplan–Meier (KM) method and compared using log‐rank test. Stata 14
(Stata, College Station, TX, USA) was used for all the analyses and statistical tests were 2‐
sided with significance level set at 0.05.
3. Results
3.1. Patient Characteristics
One hundred and two patients (102/340, 30%) discontinued maintenance therapy be‐
fore three years (early group) vs. 238/340 (70%) patients who continued therapy after three
years (late group). The groups were well matched in their baseline characteristics of age,
gender, ISS staging, cytogenetics, response before transplant, and melphalan dosing (Ta‐
ble 1). The median age of the patients in the early group was 58 years and 60 years in the
late group. About 20% (69/340) of patients in both groups were older than 65 years. More
patients in the late group were African American (15.5% vs. 5.9%, p = 0.02). In the early
group, (32/102, 36.8%) and (67/238, 32.8%) in the late group had high risk cytogenetics
defined as gain 1 q, t (4:14), t (14:20), t (14:16) or deletion 17 p. Melphalan was used for
conditioning before transplant. Most patients (311/340) received melphalan 200 mg/m2.
More than half of the patients in both groups had achieved complete remission or very
good partial response before transplant. In the post‐transplant disease assessment, pa‐
tients in the late group were more likely to have achieved a CR/VGPR before starting
maintenance therapy (86.6% vs. 78.4%, p = 0.01). The choice of maintenance therapy was
per treating physician discretion. Table 2 shows details of maintenance regimens and the
most common reasons for discontinuation of maintenance therapy. The most common
maintenance regimens were lenalidomide (304/340, 89.4%) and bortezomib (36/340,
10.5%).
The most common reason for stopping treatment in the early group was adverse
events related to medication (50.0%) and patient preference (22.5%) (Table 2). Most of the
adverse events were hematological events, especially neutropenia and febrile neutro‐
penia. Fatigue and diarrhea were the most common non‐hematological side effects (Table
3). On the other hand, progression of disease (23.9%) and adverse events (12.6%) were the
most common reasons for discontinuing maintenance in late group. There were nine SPM
events, four (3.9%) in the early group and five (2.1%) in the late group. Two patients de‐
veloped AML, two B‐cell ALL, one prostate cancer, one adenocarcinoma of the lung, one
EBV associated lymphoma, and two developed unknown SPM. At the time of the last
follow‐up, 131/238 (55.0%) patients in the late group were still on their maintenance ther‐
apy.
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Table 1. Baseline characteristics of patients.
Maintenance < 3 Years
(n = 102), 30%
Age at Transplant (Yrs, me‐
dian range)
Age ≤65
Age >65
Sex
Male
Female
Race
Black
White
Others
Melphalan use
140
200
Pre‐Transplant remission sta‐
tus
CR/VGPR
PR
SD/PD
Post‐Transplant remission sta‐
tus
CR/VGPR
PR
SD/PD
Cytogenetic risk
Standard risk
High/Intermediate risk
ISS staging
1
2
3
Maintenance ≥ 3 Years
(n = 238), 70%
p‐Value
58
37–73
60
37–75
0.33
83
19
81.4
18.6
188
50
79.0
21.0
0.62
57
45
55.9
44.1
141
97
59.2
40.8
6
96
0
5.9
94.1
0.0
37
197
4
15.5
82.8
1.7
12
90
11.8
88.2
27
211
11.3
88.7
0.56
0.02
0.91
0.15
55
38
9
53.9
37.3
8.8
153
64
21
64.3
26.9
8.8
0.01
80
14
8
78.4
13.7
7.8
206
29
3
86.6
12.2
1.3
55
32
63.2
36.8
137
67
67.2
32.8
44
23
15
53.7
28.0
18.3
78
76
48
38.6
37.6
23.8
0.52
0.07
Table 2. Maintenance regimens and reasons for stopping maintenance therapy.
Maintenance Drugs
Lenalidomide
Bortezomib
Ixazomib
Lenalidomide + Bortezomib
Lenalidomide + Cyclophos‐
phamide
Pomalidomide
Pomalidomide + Cyclophos‐
phamide
Thalidomide
Prednisone
Reasons for stopping *
Patient Preference
Physician Decision
Maintenance < 3 Years
(n = 102)
n
%
90
88.2
15
14.7
0
0
0
0
Maintenance ≥ 3 Years
(n = 238)
n
%
214
89.9
21
8.8
12
5.0
2
0.8
0
0
2
0.8
0
0
3
1.3
0
0
1
0.4
3
3
2.9
2.9
1
1
0.4
0.4
23
1
22.5
1
7
0
2.9
0
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Progression
Recurrent Infection
SPM
Adverse events
Other
0
1
4
51
22
0
1
3.9
50
21.6
57
0
5
30
8
23.9
0
2.1
12.6
3.4
* 131 patients in maintenance ≥ 3 years group were still on maintenance at last follow up.
Table 3. Adverse events.
Adverse Events
Pancytopenia
Neutropenia
Infection
Thrombocytopenia
GI
Neurologic deficits
Cardiac
Depression
Fatigue
Neuropathy
Peripheral neuropathy
Renal
Skin
DVT or pulmonary embolism
Maintenance < 3 Years
8
7
9
1
8
1
1
1
10
5
2
2
3
0
Maintenance ≥ 3 Years
2
5
2
0
4
0
4
0
9
4
0
1
0
1
3.2. Survival Outcomes
The median PFS in the early group was 5.1 years (95% CI: 4.4–7.4), and median OS
was 9.8 years (95% CI: 8.2‐ to NR). In the late group, median PFS was not reached (95%
CI: 8.5‐ NR) and median OS was not reached. Among those alive at the last contact, the
median follow‐up was 5.4 years and 6.1 years for early maintenance and late maintenance
groups, respectively. The late group had significantly longer PFS and OS than the early
group, with a 5‐year estimated PFS of 80% (95% CI: 74–85%) vs. 50% (95% CI: 39–60%) (p
< 0.001), and 5‐year OS of 96% (95% CI: 92–98%) vs. 79% (95% CI: 69–86%) (p < 0.001)
(Table 4 and Figure 1). After adjusting for race, post‐transplant remission status, and ISS
staging, the hazard ratio for risk of relapse was HR = 0.31, 95% CI: 0.21–0.45; and hazard
ratio for risk of death was HR = 0.34, 95% CI: 0.18–0.64. Furthermore, we performed PFS
and OS analyses including only the patients who were in CR/VGPR before starting
maintenance therapy to evaluate the benefit of the continuous maintenance therapy in
these subsets. The late group still had significantly longer PFS and OS than the early
group, (p < 0.001) (Figure 2).
Table 4. Progression free and overall survival.
Maintenance < 3 Years
Rate
95% CI
Overall survival
(OS)
Year 1
100%
Year 3
94%
Year 5
79%
Year 10
45%
Median, 95% CI
9.8
87%
69%
26%
8.2
97%
86%
62%
NR
Maintenance ≥ 3 Years
Rate
95% CI
100%
100%
96%
71%
NR
92%
52%
NR
98%
84%
NR
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Progression free
survival (PFS)
Year 1
100%
Year 3
81%
Year 5
50%
Year 10
13%
Median, 95% CI
5.1
72%
39%
5%
4.4
87%
60%
25%
7.4
0.00
0.25
Probability
0.50
0.75
1.00
(A)
(B)
Figure 1. Survival outcomes from the date of transplantation.
99%
98%
80%
51%
NR
97%
95%
74%
38%
8.5
100%
99%
85%
63%
NR
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Figure 2. Survival outcomes among patients with CR/VGPR before starting maintenance therapy.
4. Discussion
Maintenance therapy after stem cell transplant is an integral part of the management
of multiple myeloma [26,27]. However, in a clinical setting, there are many factors that
can halt uninterrupted maintenance [28,29]. In this retrospective study, we analyzed data
from 340 patients at our institution who had received autologous transplant and who re‐
ceived maintenance for at least six months. We found that the patients receiving more
than three years of maintenance therapy were more likely to have longer progression‐free
survival and overall survival.
Lenalidomide was the most commonly used maintenance therapy in our patient co‐
hort. Lenalidomide has been extensively tested in phase III clinical trials. In the landmark
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IFM−05 trial comparing lenalidomide maintenance to placebo following ASCT, improved
PFS was seen in the maintenance arm (41 months vs. 23 months, p < 0.001). OS was similar
in both groups. However, lenalidomide was stopped after two years due to a higher inci‐
dence of SPM [22,25]. Similarly, in the ALLIANCE 10,014 study, 460 patients were ran‐
domized after ASCT to receive 10 mg of lenalidomide 100 days post‐ASCT. The study was
unblinded in 2009 when the benefit of lenalidomide maintenance became apparent, and
the remaining patients were crossed over to the lenalidomide arm. Progression‐free sur‐
vival at 34 months of follow‐up was 37% vs. 58% in the placebo arm (p < 0.001). OS in both
groups was 85% vs. 77% (p = 0.03) (21). In a long‐term follow‐up with a median duration
of 91 months, PFS and OS continued to be longer in the lenalidomide group compared to
the placebo group with HR = 0.57 (95% CI: 0.46–0.71; p < 0∙0001) for PFS and HR = 0.61
(95% CI: 95% CI 0.46–0.80; p = 0∙00040) for OS. The cumulative incidence of SPM was
higher in the lenalidomide group (HR = 2.34; 95% CI: 1.29–4.23; p = 0∙0073) [30]. Lenalido‐
mide maintenance is endorsed by ASTCT, NCCN, and ESMO guidelines after autologous
transplant [24,26,27].
The second most commonly used drug in our cohort for maintenance was borte‐
zomib, which was given to 10% of patients. Bortezomib as maintenance therapy adminis‐
tered every two weeks was studied in HOVON−65/GMMG‐HD4 trial after vincristine,
adriamycin, and dexamethasone (VAD) vs. bortezomib, adriamycin, and dexamethasone
(PAD) induction. The maintenance arms consisted of either thalidomide for the VAD arm
vs. bortezomib for the PAD arm. In a long‐term follow‐up analysis, bortezomib mainte‐
nance delayed progression with median PFS of 34 months vs. 28 months [23]. ASTCT
guidelines recommend maintenance bortezomib in patients with high‐risk cytogenetics
[24].
The most common reason for discontinuation of maintenance treatment was adverse
events in the early discontinuation population. This is consistent with previously pub‐
lished data in clinical trials. IFM−05 saw 27% of patients discontinuing lenalidomide due
to adverse events [25]. The HOVON 64/GMMG4 trial saw 11% of patients discontinuing
treatment for any adverse event [23]. In our patients, the most common adverse events
were neutropenia and fever/infection. Other notable events were fatigue, diarrhea, and
low blood counts. These are well described adverse effects of lenalidomide in clinical trials
[25]. Some patients developed neuropathy with bortezomib.
The duration of PFS and OS were longer in our study than described in clinical trials
previously [25,30]. However, we did exclude patients with early disease progression in
order to match the groups and avoid the confounding effect of early progression on PFS
and OS in the early discontinuation group. If we had included those patients, a large pro‐
portion of early discontinuation would be due to disease progression and would have
even shorter PFS and likely shorter OS. When comparing the groups, our study still
demonstrated longer PFS and OS in patients who continued their maintenance beyond
three years, due to the depth of response with maintenance therapy.
There are limitations in our study. The retrospective design could introduce selection
bias into our patient cohort. The majority of the patients in this study were on lenalido‐
mide maintenance; therefore, the study is under‐powered to analyze the differences in
survival outcomes based on maintenance strategies or cytogenetic abnormalities. Moreo‐
ver, this is a single center study that spans from 2005 to 2016, and there may have been
changes in supportive care that may have an impact on outcomes. The introduction of
daratumumab has changed the landscape of myeloma treatment and daratumumab
maintenance as studied in CASSIPOEIA and GRIFFIN trials [31,32]. The use of measura‐
ble residual disease (MRD) to guide the maintenance treatment is also in clinical trials and
may be used in future to guide the decision making and change the landscape of myeloma
treatment [33–35]. Nonetheless, our study supports prior data that continuous mainte‐
nance leads to better survival outcomes.
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5. Conclusions
Maintenance treatment in myeloma is standard of care after autologous transplant.
Longer duration of maintenance treatment is associated with better PFS and OS. Although
our study is a retrospective analysis with a selection of patients who could tolerate at least
six months of therapy, it showed progression‐free and survival advantage of continuous
maintenance. Although, side effects can be limiting every effort should be made to con‐
tinue maintenance therapy. Strategies such as decreasing maintenance dose, or switching
therapy, may enhance medication tolerance and thus extend a patient’s total time on
maintenance therapy. This may benefit their treatment with a deepened response.
Author Contributions: Conception and design: D.M.B., Y.A.E., N.S. Collection and assembly of
data: J.N., F.C., N.S., P.E., Y.A.E., A.R., N.B., A.K., S.D., E.U. Data analysis and interpretation: Q.Z.,
N.S., Y.A.E. Manuscript writing: N.S., Y.A.E., M.S.F. Scientific input and critical comments: All au‐
thors. All authors have read and agreed to the published version of the manuscript.
Funding: FC was supported by the Elsa U. Pardee Foundation, the International Myeloma Society and
Paula and Rodger Riney Foundation Translational Research Award, and the Pelotonia Foundation.
Institutional Review Board Statement: The study was conducted in accordance with the institu‐
tional guidelines with approval of the institutional review board (2019E0065).
Informed Consent Statement: Patient consent was waived as this was a retrospective chart review
study.
Data Availability Statement: The data presented in this study are available on request.
Conflicts of Interest: The authors declare no conflict of interest.
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