International Journal of Clinical Medicine, 2011, 2, 570-575
doi:10.4236/ijcm.2011.25094 Published Online November 2011 (http://www.SciRP.org/journal/ijcm)
1
Efficacy of Long-Term Treatment with Low-Dose
Thalidomide for Patients with Relapsed/Refractory
Multiple Myeloma
Kazuyuki Shimizu1, Hirokazu Murakami2, Morio Sawamura3, Yutaka Hattori4, Shinichiro Okamoto5,
Akiyoshi Miwa6, Isamu Sugiura7, Chihiro Shimazaki8, Masafumi Taniwaki8, Tadao Ishida9, Toshiaki
Hayashi9, Hiroshi Kosugi10, Masaaki Yuge10, Shinsuke Iida11, Takashi Ishida11, Kazutaka Sunami12,
Hideki Asaoku13, Akira Sakai14, Masahiro Abe15, Toshiyuki Takagi16
1Department of Multimodal Therapy for Multiple Myeloma, Aichi Gakuin University School of Dentistry, Nagoya, Japan; 2Course of
Health Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan; 3Nishi-Gunma Hospital, Shibukawa,
Japan; 4Division of Pharmacy, Keio University School of Medicine, Tokyo, Japan; 5Division of Hematology, Keio University School
of Medicine, Tokyo, Japan; 6National Center for Global Health and Medicine, Tokyo, Japan; 7Toyohashi Municipal Hospital, Toyo-
hashi, Japan; 8Kyoto Prefectural University of Medicine, Kyoto, Japan; 9Sapporo Medical University, Sapporo, Japan; 10Ogaki Mu-
nicipal Hospital, Ogaki, Japan; 11Department of Medical Oncology and Immunology, Nagoya City University, Nagoya, Japan;
12Okayama Medical Center, Okayama, Japan; 13Hiroshima Red Cross Hospital, Hiroshima, Japan; 14Department of Hematology and
Oncology, Hiroshima University, Hiroshima, Japan; 15Deaprtment of Medicine and Bioregulatory Sciences, Tokushima University,
Tokushima, Japan; 16Kimitsu Chuou Hospital, Kisarazu, Japan.
Received August 11th, 2011; revised September 20th, 2011; accepted October 14th, 2011.
ABSTRACT
Introduction: We report the results of a prospective study of long-tern treatment with single-agent thalidomide in pa-
tients who had responded in a preceding trial of the use of thalidomide for relapsed/refractory myeloma. Patients and
Methods: Nineteen patients were enrolled: 11 patients (57.9%) treated at a dosage of 100 mg/day; 2 patients (10.5%)
at a dosage of 200 mg/day; 2 patients (10.5%) at a dosage of 300 mg/day; and 4 patients (21.1%) at a dosage of 400
mg/day. The median follow-up from the start of the preceding study was 3.0 years. At the time of entry to this study, 5
patients (26.3%) had partial response (PR), another 5 patients (26.3%) had a minimal response (MR), and the remain-
ing 9 patients (47.4%) had shown no chang e (NC). Results: The cumulative MR rate was 78.9% (at the 32nd week) and
the cumulative PR rate was 47.4% (at the 112th week). The median progression-free survival was 104 weeks and the
median time to next treatment was 144 weeks. No patients experienced grade 4 or greater hematologic toxicity or grade
3 or greater non-hematologic toxicity. Conclusion: Long-term thalido m ide maintenan ce therapy indu ced an increa se in
response rate, suppressed the progression to active myeloma without severe adverse events, and contributed to long
survival with good activities of daily living.
Keywords: Maintenance Therapy, Progression-Free Survival, Time to Next Treatment, Efficacy, Safety
1. Introduction
Whereas the positive role of thalidomide as a consolida-
tion treatment after high-dose therapy with autologous
stem cell transplantation (HDT-ASCT), in the context of
newly diagnosed myeloma, has been clarified in the pa-
tients without high-risk cytogenetics who have obtained
less than a very good partial response [1,2], its role as a
maintenance therapy remains controversial because of its
toxicity and the concern of potential induction of resis-
tance to subsequent treatment [3-5]. In addition, we cur-
rently have much less information on the role of thali-
domide as maintenance therapy, in the context of cases
of relapsed/refractory multiple myeloma, after successful
salvage treatment. Based on the results of phase II trials
in which the cumulative dose of thalidomide did not have
an impact on the efficacy of maintenance therapy and to-
xicity increased above a dosage of 200 mg/d [6,7], treatment
with low-dose thalidomide is now the preferred option.
We have conducted a prospective study to evaluate the
efficacy and safety of thalidomide given as a single-agent
maintenance therapy to patients with relapsed and/or re-

Efficacy of Long-Term Treatment with Low-Dose Thalidomide for Patients with 571
Relapsed/Refractory Multiple Myeloma
fractory multiple myeloma who had been enrolled in a
previous phase II study [8] and who achieved at least no
change (NC) with thalidomide treatment as per the study
protocol.
2. Patients and Methods
2.1. Eligibility
Patients were deemed eligible for enrollment in this study
if they had responded and maintained at least NC as-
sessed at the 16th week of the phase II study period with
single-agent thalidomide treatment given for at least 4
weeks [8]. According to the phase II study protocol, pa-
tients who achieved at least a minimal response (MR)
continued on thalidomide treatment at the dosage with
which the response had been obtained until the cutoff of
the study. Otherwise, the dose of thalidomide was esca-
lated by 100 mg every 4 weeks until the cutoff of the stu-
dy (16th week) to a maximum of 400 mg/d. In total, 19
patients had achieved and maintained a response of at
least NC according to the European Group for Blood and
Marrow Transplantation response criteria [9] by the cut-
off of the phase II study and were studied.
All patients gave written informed consent and agreed
to abide by strict contraception. The study and the writ-
ten informed consent form were approved by the institu-
tional review board of each participating hospital. The
study was conducted in accordance with the Good Clini-
cal Practice for Trials of Drugs and the Declaration of
Helsinki.
2.2. Treatment Schedule
Single-agent thalidomide treatment was continued in the
19 patients at their individual final doses of the phase II
study until disease progression or intolerance occurred,
for a maximum of 3 years. Patients were evaluated every
4 weeks for response and drug toxicity. Thalidomide was
supplied by the Fujimoto Pharmaceutical Corporation (O-
saka, Japan) and was given orally before sleep. No anti-
thrombotic prophylaxis was instituted because no patients
experienced thromboembolic events during the phase II
study.
2.3. Response, Progression-Free Survival, Time
to Next Ttreatment, and Toxicity Criteria
Responses were assessed by the decrease in the mono-
clonal protein measured at the time of entry into the pha-
se II study using the European Group for Blood and Mar-
row Transplantation response criteria [9]. Progressionfree
survival (PFS) was measured from the date of initiation
of thalidomide treatment in the phase II study until death
or disease progression, whichever was earlier. Time to next
treatment (TTNT) was measured from the date of initia-
tion of thalidomide treatment until death or the date of
initiation of the next treatment. The PFS and TTNT
curves were constructed according to the Kaplan-Meier
method. Toxicities were graded using the National Can-
cer Institute Common Toxicity criteria (version 3).
3. Results
3.1. Patient Characteristics
A total of 19 patients were enrolled between December
2005 and April 2006. Patients were followed until March
2009 and the median follow-up from the start of the pha-
se II study was 3 years (156 weeks; range, 28 - 180 weeks).
The characteristics of the 19 patients are shown in Table
1. The mean age was 60 years (range, 42 - 81 years). More
than half of the patients had relapsed after HDT-ASCT.
Eleven patients (57.9%) were treated with thalidomide
at a dosage of 100 mg/day, 2 patients (10.5%) were treated
at a dosage of 200 mg/day, 2 patients (10.5%) were treated
at a dosage of 300 mg/day, and 4 patients (21.1%) were
treated at a dosage of 400 mg/day.
3.2. Response
At the time of entry to this study, 5 patients (26.3%) had
partial response (PR), another 5 patients (26.3%) had MR,
Table 1. Patients characteristics.
Variables Total
Number of cases 19
Mean age (yr) 60.0
Range (yr) 42 - 81
Time sinceDx(yr) 5.03
Range (yr) 0.17 - 17
Sex (male/female) 8/11
M protein type
IgG 12
IgA 6
Light chain 1
PS (0/1/2) 15/3/1
ISS stage (I/II/III) 11/3/5
Prior therapy
Chemotherapy 8
Lines (median, range) 1.5, 1 - 3
ASCT 11
β 2M (mg/L) median, range 2.50, 1.0 - 10.24
LDH (IU/L) median, range 162.5, 105 - 346
Dx; diagnosis, PS; performance status, β2M; β2 microgobulin.

Efficacy of Long-Term Treatment with Low-Dose Thalidomide for Patients with
572
Relapsed/Refractory Multiple Myeloma
and the remaining 9 patients (47.4%) had shown NC to
the latest thalidomide therapy.
The cumulative response rate is shown in Figure 1.
The reduction of M-protein was continued at the 112th
week. MR was obtained in 73.7% at the 24th week and in
78.9% at the 32nd week. PR was obtained 31.6% at the
24th week, 31.6% at the 32nd week, 42.1% at the 48th
week, and 47.4% at the 112th week.
3.3. Progression-Free Survival
Figure 2 shows the PFS curve of the 19 patients studied;
the median PFS was 104 weeks (1.99 years). The PFS ra-
tes were 73.0% at 1 year, 55.1% at 2 years, and 28.0% at
3 years. Only 1 patient has died on the 31st week.
3.4. Time to Next Treatment
Figure 3 shows the TTNT curve of the 19 patients. The
median TTNT was 144 weeks (2.76 years). The TTNT rate
was 73.7% at 1 year, 63.2% at 2 years, and 47.4% at 3
years. Thalidomide/high-dose dexamethasone treatment
was conducted in 6 patients and melphalan/prednisolone/-
thalidomide treatment was conducted in 3 patients after
the discontinuance of single-agent thalidomide mainte-
nance therapy. Eight patients continued single-dose tha-
lidomide treatment over 40 months after progressive di-
sease. Thalidomide was discontinued in only 2 patients.
3.5. Toxicities
All 19 patients experienced at least Grade 1 toxicity; how-
ever, no patient experienced Grade 4 or greater hema-
Figure 1. The cumulative response rate in patients treated
with long-term thalidomide maintenance. The black line
shows minimal response rate and the gray line shows par-
tial response rate.
Figure 2. Progression-free survival in patients treated with
long-term thalidomide maintenance. The curve was cons-
tructed according to the Kaplan-Meier method.
Figure 3. Time to next treatment in patients treated with
long-term thalidomide maintenance. The curve was cons-
tructed according to the Kaplan-Meier method.
tologic toxicity or Grade 3 or greater non-hematologic
toxicity. The toxicity profile observed in at least 10 pa-
tients is shown in Table 2. The most common Grade 3
hematologic toxicities were neutropenia in 9 patients
(47.4%), lymphopenia in 5 (26.3%), and leucopenia in 4
(21.1%). The most common Grade 2 non-hematologic
toxicities were peripheral neuropathy in 3 patients (15.8%),
constipation in 2 (10.5%), and skin rash in 2 (10.5%).
One patient receiving 200 mg/d thalidomide but no throm-
boprophylaxis experienced deep vein thrombosis on the
71st week.
Toxicity or intolerance that resulted in the disconti-
nuation or dose reduction of thalidomide occurred in 4 of

Efficacy of Long-Term Treatment with Low-Dose Thalidomide for Patients with
Relapsed/Refractory Multiple Myeloma
573
Table 2. Toxicity profile.
n (%)
Toxicity Total Grade 1 Grade 2 Grade 3
Hematological
Neutropeni 14 (73.7) 1 (5.3) 4 (21.1) 9 (47.4)
Lymphopenia 10 (52.6) 1 (5.3) 4 (21.1) 5 (26.3)
Leucopenia 10 (52.6) 2 (10.5) 4 (21.1) 4 (21.1)
Basophilia 11 (57.9) 11 (57.9) 0 0
Non-hematological
Constipation 16 (84.2) 14 (73.7) 2 (10.5) 0
Peripheral neuropathy 15 (78.9) 12 (63.2) 3 (15.8) 0
Somnolence 14 (73.7) 13 (68.4) 1 (5.3) 0
Dry mouth 11 (57.9) 11 (57.9) 0 0
Edema 10 (52.6) 10 (52.6) 0 0
Tremor 10 (52.6) 10 (52.6 0 0
Skin rash 10 (52.6) 8 (42.1) 2 (10.5) 0
the 19 patients (21.1%). These 4 patients were treated
with thalidomide at a dosage of over 200 mg/day. Tha-
lidomide treatment was discontinued in 2 patients: deep
vein thrombosis occurred in 1 patient treated with 200
mg/d on the 71st week, and nephrotic syndrome occurred
in 1 patient on the 132nd week. Thalidomide dosage was
reduced in another 2 patients because of peripheral neu-
ropathy and neutropenia. No patients treated with 100
mg/d thalidomide discontinued treatment due to toxicity.
4. Discussion
This study was conducted prospectively to evaluate the
efficacy and safety of long-term treatment with single-
agent thalidomide in patients who had been enrolled and
obtained at least NC in a phase II trial of the use of tha-
lidomide in patients with relapsed/refractory multiple mye-
loma [8]. The dosage of thalidomide in this continuous
treatment study was determined by the one with which
each patient had responded by achieving at least NC in
the preceding phase II trial.
Nineteen patients were enrolled. Eleven patients (57.9%)
were treated with continuous thalidomide treatment at a
dosage of 100 mg/day, 2 patients (10.5%) were treated at
a dosage of 200 mg/day, 2 patients (10.5%) were treated
at a dosage of 300 mg/day, and 4 patients (21.1%) were
treated at a dosage of 400 mg/day. The discontinuation
or dose reduction of thalidomide occurred in 4 patients
(21.1%). These 4 patients were treated with thalidomide
at a dosage of over 200 mg/day. In contrast, no patients
treated with 100 mg/d discontinued thalidomide due to
toxicity. According to these findings, low-dose thalido-
mide might be adequate for the maintenance treatment
for multiple myeloma.
The beneficial effect of long-term treatment with tha-
lidomide was observed at least until week 112 (2.15
years). The PR rate was 26.3% at the time of initiation of
maintenance treatment (16th week) and continuously in-
creased up to 47.4% at the 112th week. The MR rate also
increased from 26.3% at the initiation of maintenance
treatment to 78.9% at the 32nd week. Singhal et al. re-
ported that the response of thalidomide treatment was
obtained within 4 months in patients with refractory mye-
loma [10]; however, our study revealed the response of
long-term thalidomide maintenance treatment gradually
increased over 4 months after initiation of thalidomide.
The PFS was fairly long in this study. It is difficult to
compare this result with those in the published reports on
single-agent thalidomide treatment in cases of relapsed/
refractory multiple myeloma, because most trials used a
starting thalidomide dose of 200 mg/d and utilized a dose
escalation up to 800 mg/d, and also because the follow-
up period is not as long as that in our study [6,11]. The
case series studied may be mostly composed of low-risk
patients in terms of age, International Staging System stages,

Efficacy of Long-Term Treatment with Low-Dose Thalidomide for Patients with
574
Relapsed/Refractory Multiple Myeloma
2-microglobulin levels, and lactate dehydrogenase lev-
els. Recent studies have shown the importance of ob-
taining complete response (CR) not only in patients with
newly diagnosed multiple myeloma but also relapsed/-
refractory multiple myeloma [12,13]. However, in patients
in the low-risk category, survival is not significantly dif-
ferent between patients with CR and those with PR [14].
Another recent study has disclosed that maintaining CR
is more important than obtaining CR in terms of longer
survival duration [15]. It is also noted that patients with
low-risk disease can survive longer with PR status [14].
In our patients, long-term maintenance treatment with
thalidomide upgraded the initial response status and sus-
tained the upgraded response status, which resulted in
prolonged PFS.
The TTNT was extremely long compared with the
PFS. Eight patients continued single-dose thalidomide
treatment after progressive disease because of the absen-
ce of progression to active myeloma, namely clinical re-
lapse [16]. According to this finding, one of the reasons
for the long TTNT might depend on the slow progression
to active myeloma during thalidomide maintenance treat-
ment. Our results are in agreement with the comment of
Stewart [17] that, in a slower-tempo relapse, sequencing
of drugs may offer superior overall survival results.
With regard to a long-term treatment with thalidomide,
there has been a concern of the late development of neu-
ropathy if given sufficient length of time with low-dose
thalidomide [18]. However, long-term treatment with
low-dose thalidomide for as long as 3 years in the pre-
sent study did not result in delayed development of ad-
verse events. Furthermore, because of the lower toxicity
of low-dose thalidomide, the patients could stay on the
treatment and enjoyed a long-term survival with good ac-
tivities of daily living.
5. Acknowledgements
We thank the patients who agreed to participate in this
study.
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