International Journal of Myeloma 5(1): 8–14, 2015
©日本骨髄腫学会

ORIGINAL

Post-marketing surveillance of the treatment with THALED® CAPSULE
in patients with relapsed/refractory multiple myeloma
Hirokazu MURAKAMI1, Kazuyuki SHIMIZU2 and Toshiyuki TAKAGI3THALED® CAPSULE (thalidomide) was approved as a drug for relapsed/refractory multiple myeloma (MM) in October
2008 in Japan. Because the number of patients included in the domestic clinical study was small, the postmarketing surveillance was necessary and was conducted accordingly. This study included 1,548 patients during aperiod from February 2009 to February 2010. The mean age was 68.5 years, and the male/female ratio was 1.03.
Mean disease duration was 3.8 years from the diagnosis of myeloma. Almost all patients (98.5%) were treated at adosage below 200 mg/day. All grade and serious adverse events (AEs) were observed in 58.6% and 8.7%, respectively. The incidence of these AEs was lower than that observed in the previous domestic clinical study; however themonitoring and audit was not performed in this surveillance, so that the low grade AEs might have been missed.
Main AEs were peripheral neuropathy, constipation, somnolence and leukopenia. Serious AEs were leukopenia,
pneumonia, neutropenia and peripheral neuropathy. Venous thromboembolism (VTE) was observed only in 1.4%.
Median overall survival was not reached, and median duration of treatment was 24.0 weeks. It is difficult to compare
the present data with the other data because this is a post-marketing surveillance. However, the incidence of AEs,
especially VTE, was obviously lower than that reported in western countries, so that THALED® CAPSULE can be usedsafely in clinical practice of Japanese MM patients.
Key words:

myeloma, thalidomide, adverse event, venous thromboembolism, peripheral neuropathy

Introduction

Thalidomide was introduced to the market in the 1950s as
a sedative. However, Lenz 4) disclosed a close relationship

Multiple myeloma is a clonal plasma cell disorder account-­between the exposure to thalidomide in pregnant womening for 10% of hematological malignancies. Melphalan plus

and the development of phocomelia (flipper-like limb) in theirprednisone treatment has been the mainstay of myeloma

neonates in 1961. In 1994, D’Amato et al. 5,6) showed thattreatment since the 1960s. Approximately 50% of patients­thalidomide inhibited angiogenesis in the experiments using

respond to this treatment, however, responses were not dura-

rabbits and suggested thalidomide as a possible therapeuticble and the median overall survival (OS) was only three years 1).

agent for diseases that show increased angiogenesis, particu-

The median OS has now been improved by high-doselarly for malignant tumors. After the report, clinical trials withchemotherapy with autologous stem cell transplantation 2).
­

thalidomide were initiated in many countries testing the

Additionally, novel agents including immunomodulatory drugs­possibility as a new therapeutic agent for multiple myeloma(thalidomide and lenalidomide) and proteasome inhibitor(MM) patients, and the effectiveness of thalidomide is now(bortezomib) have provided further improvement in the out-

well established in not only relapsed/refractory but also newly

come of myeloma treatment 3).

diagnosed ­patients 7,8).

Received: October 6, 2014, accepted: November 8, 2014
1
Gunma University Graduate School of Health Sciences2
Tokaichuo Hospital
3
Kimitsu Chuou Hospitalfor relapsed/refractory MM in October 2008 in Japan. Because

THALED® CAPSULE (thalidomide) was approved as a drug

Corresponding author: Hirokazu MURAKAMI
Gunma University Graduate School of Health Sciences, 3-39-15
Showa-machi, Maebashi, Gunma, Japan
TEL & FAX: +81-27-220-8973
E-mail: hmura@gunma-u.ac.jp

8International Journal of Myeloma

vol. 5 no. 1 (2015)

the number of patients in the domestic clinical study was small
and limited, the post-marketing surveillance was necessary
and was conducted for all patients taking THALED® CAPSULE
to comply with the request of the regulatory authority. We
herein report the interim analysis of the data of the patients
who were treated in THALED® CAPSULE collected by the endof December 2013.

Post-marketing surveillance of THALED® CAPSULE

Patients and Methods
This study included 1,548 patients (from 331 institutions)

Results
Patient characteristics

treated during a period from its launch (February 2009) to Feb-

The characteristics of the 1,548 patients are shown in Table 1.

ruary 2010, and focused on the efficacy and its adverse events.

All patients were diagnosed as refractory/relapsed MM. The

Patients were followed until discontinuation of the treatment,

median age was 69.0 years (range: 33–93 years), and male/otherwise up to 104th weeks.

female ratio was 1.03 (787/761 cases). The median disease

Toxicities were graded according to the Article 253 of thePharmaceutical Affaires Law Enforcement Regulations.

duration from the initial diagnosis was 2.9 years (range: 0–25
years). About 20% of the patients had relapsed after high-dose

The responses obtained by 16th weeks from the start ofchemotherapy with autologous stem cell transplantation. The

THALED® CAPSULE treatment were assessed by the maximum

number of patients with PS 0, 1, 2, 3, and 4 was 413 (26.7%),

decrement of monoclonal protein (M-protein) and are defined624 (40.3%), 303 (19.6%), 161 (10.4%), and 45 (2.9%) patients,

as: complete response (CR); negative immunofixation of therespectively.

serum and urine, partial response (PR); ≥50% reduction of

One hundred thirty-one patients (8.5%) were treated with

M-protein, minor response (MR); ≥25% reduction of M-protein,

THALED® CAPSULE at a dosage of 50 mg/day or less, 1,208

no change (NC); <25% reduction of M-protein, and progressive

patients (78.0%) at a dosage of 100 mg/day or less, and 186

disease (PD); ≥25% increase of M-protein. In patients without

patients (12.0%) at a dosage of 200 mg/day or less at the time

detectable M-protein, the response was assessed by the sizeof the last visit. Almost all patients (98.5%) were treated at aof plasmacytoma and bone marrow plasmacytosis. Duration

dosage below 200 mg/day.

of treatment (DOT) was measured from the date of initiationof THALED® CAPSULE treatment until death or discontinuation

Adverse eventsof the treatment, whichever happened earlier. Overall survival

The toxicity profile observed in at least 3% of patients is(OS) was measured from the date of initiation of THALED®

shown in Table 2. All grade and serious adverse events (AEs)

CAPSULE treatment until death or last seen, whichever cameearlier.
Statistical analysis was performed using SAS version 9.2.
The p value of less than 0.05 was considered statistically sig­
nificant.
The association of the incidence of all grade AEs wasassessed using either t-test (age), χ2-test (immunoglobulin
subtype, performance status (PS) and previous treatment­regimens), Wilcoxon (disease duration) or Fisher’s exact
test (gender, renal and liver dysfunction). Cochran-MantelHaenszel test was used to examine the difference of the incidence of VTE in patients either with or without VTE risk factors,
adjusted for the use of prophylactic agents. Fisher’s exact
test was used to examine the difference of the incidence of
peripheral neuropathy in patients either with or without
previous bortezomib treatment, and the difference of the­­incidence of VTE in patients either with or without the use ofprophylactic agents. Effectiveness was also assessed using
either t-test or Wilcoxon, and χ2-test or Fisher’s exact test wasused as safety assessment. The DOT and OS curves were­constructed according to the Kaplan-Meier method, and differences between the survival curves were tested for statisticalsignificance using the log-rank test.
This study was supported for data collection and statisticalanalysis by Fujimoto Pharmaceutical Corporation in Osaka,and the authors evaluated the safety and effectiveness of
THALED® CAPSULE.

Table 1.

Patient characteristics

Gender (male/female)Age (mean ± SD) years
Disease duration (mean ± SD) years
Ig isotype
IgG (%)IgA (%)IgD (%)
IgE (%)
IgM (%)
Light-chain myeloma (%)
Non-secretary (%)
unknown (%)
Performance status
0/1/2/3/4/unknown(%)
Renal dysfunction*+/– (%)
Liver dysfunction*+/– (%)
Past treatment
ASCT (%)
1 regimen (%)
2 regimen (%)
3 regimen (%)>4 regimen (%)
unknown (%)

787/76168.5 ± 10.0
3.8 ± 3.4
919 (59.4)
336 (21.7)
46 (3.0)
1 (0.1)8 (0.5)187 (12.1)
49 (3.2)
2 (0.1)
413/624/303/161/45/2(26.7/40.3/19.6/10.4/2.9/0.1)
307/1,241 (19.8/80.2)
87/1,461 (5.6/94.4)
348 (22.5)
404 (26.1)
336 (21.7)
240 (15.5)
178 (11.5)
42 (2.7)

ASCT; autologous stem cell transplantation*; Renal and Liver dysfunctions are depend on decision of the physicians

International Journal of Myeloma

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9MURAKAMI et al.

were observed in 907/1,548 (58.6%) and 135/1,548 (8.7%) of

Serious AEs were leukopenia (1.3%), pneumonia (0.9%), neutro-

patients, respectively. The incidence of these AEs was lower

penia (0.6%), and peripheral neuropathy (0.6%). The incidence

than that observed in the domestic clinical study (phase I/II),of hematological toxicities, including leukopenia, thrombocy-

although it was higher in patients having a longer duration

topenia, and neutropenia, kept increasing until the 12th weeksof the disease in this study (p = 0.0166). However, there

from the start of THALED® CAPSULE treatment and became

was no difference in the incidence of AEs in relation to age

plateau thereafter. Compared with the domestic clinical study,(p = 0.5604), previous treatment regimens (p = 0.8845), or

the incidence of neutropenia in this study was extremely low,

the presence of renal (p = 0.7961) or the liver dysfunction

so that we analyzed the laboratory data in case report forms.

(p = 0.5756). Surprisingly, the incidence of AEs was significant­According to the reduction rate of neutrophil listed in NCI-CTC

ly lower in patients in poor PS status (p < 0.0001). Such

Ver.4, neutropenia was classified as Grade 0 to 4. Neutropenia

patients could not continue THALED® CAPSULE treatment,of Grade 1 and 3 were 69.8% and 27.0%, respectively. Venous

and accordingly had a significantly shorter duration of treat-thromboembolism (VTE) and serious VTE were observed in 22

ment. This shorter treatment duration might have contributed

cases (1.4%) and 13 cases (0.8%), respectively. There was noto the low incidence of AEs.

difference in the incidence of VTE regardless of VTE risk includ-

The predominant AEs were peripheral neuropathy (17.1%),

ing age (p = 0.2849), body mass index (p = 0.4180), combina-

constipation (12.3%), somnolence (7.7%) and leukopenia (7.6%).

tion with steroids (p = 0.8966)/chemotherapy (p = 0.6699), andthe presence of the complication of diabetes mellitus (p =0.9238) and infection (p = 0.5068). The incidence was signifi-

Table 2. Toxicity profile observed over 3% of patients

cantly higher in patients with previous history of cardiac

Toxicity

Non-severe (%)

Severe (%)

Total (%)

events (p = 0.0500). In addition, there was no difference in VTE

Hematological toxicity
Leukopenia
Thrombocytopenia
Neutropenia
Anemia98 (6.3)
81 (5.2)
46 (3.0)42 (2.7)

20 (1.3)
7 (0.5)10 (0.6)
5 (0.3)118 (7.6)
88 (5.7)
56 (3.6)
47 (3.0)

Non-hematological toxicity
Peripheral neuropathy
Constipation
Somnolence
Dizziness
Skin eruption
Increase of CRP
Fatigue255 (16.5)
189 (12.2)
118 (7.6)
107 (6.9)
103 (6.7)
65 (4.2)
47 (3.0)

10 (0.6)
2 (0.1)1 (0.1)1 (0.1)1 (0.1)6 (0.4)2 (0.1)265 (17.1)
191 (12.3)
119 (7.7)
108 (7.0)
104 (6.7)
71 (4.6)
49 (3.2)

incidence regardless of the adaptation of prophylaxis withaspirin (p = 0.8116). Peripheral neuropathy kept increasing
until the 17th weeks from the start of THALED® CAPSULE treatment and became plateau thereafter, and was more frequently
observed in patients who had previous bortezomib treatment(p = 0.0001).
The AEs which resulted in discontinuation of thalidomide
were shown in Figure 1. One-third of patients who experienced eruption and one-fourth of patients who experienced
peripheral neuropathy discontinued thalidomide treatment.
The incidence of constipation was high, however discontinuation rate was low (1/10).

Figure 1. The rate of adverse events and reasons of discontinuation of THALED® CAPSULE treatment.

10International Journal of Myeloma

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Post-marketing surveillance of THALED® CAPSULE

Response rate, duration of treatment and overall survival

respectively (p < 0.0001). The 2-year OS in patients with andFifteen patients (1.3%), 263 patients (22.0%), and 273 patients

without renal dysfunction were 56.7% and 74.3%, respectively(22.8%) achieved CR, PR and MR, respectively. The response(p < 0.0001). The 2-year DOT in patients with and without renal

rate higher and equal to the MR was 46.1%. The response rate

dysfunction were 7.6% and 10.6%, respectively (p < 0.0001).

above MR was significantly higher in patients with IgD type

There was significant difference in OS according to immuno-

and light chain myeloma (p = 0.0003).

globulin subtype. The 1-year OS in patients with IgG, IgA, IgD,

In 723 patients (46.7%), dexamethasone and/or anticancer
drugs were combined (Table 3). The response rate above MR
was higher in these patients (56.1%) than in patients treatedwith THALED® CAPSULE alone (37.3%) (p < 0.0001).
Median OS was not reached, and the 1-year and 2-year OS

light chain and non-secretary subtype were 84.1%, 85.0%,
68.2%, 68.3% and 81.7%, respectively (p = 0.0068) (Fig. 3E).
There was a significant difference in DOT according to age.
The 2-year DOT in patients <65 years-old and ≥65 years-old
were 16.4% and 7.4%, respectively (p = 0.0040) (Fig. 3F).

were 81.7% and 70.7%, respectively. The median DOT was 24.0
weeks, and the 1-year and 2-year DOT were 29.5% and 10.1%,

Discussion

respectively (Fig. 2).
There were significant differences in OS and DOT in regard

Between February 2009 and February 2010, 1,548 patientsto PS and renal function (Fig. 3A–D). The 2-year OS in patientswere enrolled in this post-marketing surveillance of THALED®

with PS 0, 1, 2, and 3 plus 4 were 85.0%, 81.6%, 52.9%, and

CAPSULE. It was found that almost all patients were treated

25.5%, respectively (p < 0.0001). The 2-year DOT in patientswith thalidomide below 200 mg/day. In the initial phase ofwith PS 0, 1, 2, and 3 plus 4 were 15.8%, 11.7%, 6.6%, and 1.7%,

clinical trial of thalidomide, high dose thalidomide up to 800
mg/day was recommended 7), however the efficacy and safety

Table 3. Drugs combined with THALED® CAPSULE
Drug

No. of patients (%)

dexamethasone
prednisolone
melphalanbortezomib
cyclophosphamide
doxorubicin
vincristine
methylprednisolone
others397 (25.6)
354 (22.9)
207 (13.4)
38 (2.5)
36 (2.3)
11 (0.7)
10 (0.6)
8 (0.5)16 (1.0)

Figure 2.

of low-dose thalidomide is now well established 9,10). In theJapanese domestic clinical study (phase I/II), recommended
dose was 400 mg/day or lower 11).
That the incidence of AEs was lower in this surveillance thanin the previous domestic clinical study, was probably due tothe difference of toxicity criteria and dose of thalidomide. In
addition, the monitoring and audit was not performed in thissurveillance, so that the low grade AEs might have been
missed. Regarding neutropenia, we analyzed the laboratory
data in case report forms, and found relatively high incidenceof Grade 3/4 neutropenia, so that neutropenia should have

Overall survival (OS) and duration of treatment (DOT) of all patients treated with THALED® CAPSULE.

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MURAKAMI et al.

Figure 3. A: Overall survival (OS) according to performance status. B: Duration of treatment (DOT) according to performance status. C: OS inpatients with/without renal dysfunction. D: DOT in patients with/without renal dysfunction. E: OS according to immunoglobulin subtype.
F: DOT according to age.

12International Journal of Myeloma

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Post-marketing surveillance of THALED® CAPSULE

been noted as a critical AE in Japanese patients. The incidence

PS. However, the OS in this surveillance, which did not reach toof VTE in this surveillance was apparently lower compared

the median, was very good, which might ascribe to the subse-

with the reports from U.S.A and Europe, and had been alreadyquent salvage treatments with other novel agents.

shown from Japan and other Asian countries 11–14). However, it

Conclusion

is necessary to observe carefully the patients with previous
history of cardiac events as was noted in this surveillance.
Other reported risk factors of VTE, such as age, body mass

It is difficult to compare the present data in the other clinicalindex, combination with steroids/chemotherapy, diabetes

data reported from U.S.A. and Europe because this study ismellitus, and infection, could not predict the development of

post-marketing surveillance. However, the incidence of AEs,

VTE. Prophylactic efficacy of aspirin for VTE was not observed

especially VTE, was obviously lower than that reported in U.S.A.

in this surveillance; however it is necessary to perform a pro-and Europe, so that THALED® CAPSULE can be used safely inspective study. Five patients had pulmonary embolism, andclinical practice of Japanese MM patients.

among them two patients died of it, so that VTE was one of the

Acknowledgment

most serious AEs. Long-term administration of thalidomide
and previous bortezomib treatment seem to contribute toperipheral neuropathy, accordingly a careful assessment of

We thank all patients and medical staff members in attend-

neurological complaints is required in these patients. The inci-

ing institutions who have agreed to participate in this surveil-

dence of hematological toxicities, especially neutropenia,

lance study.

increased up to the 12th weeks and became plateau there­
after. According to this data, it is necessary to check frequently

Conflict of Interest

the complete blood count until 3 months from the beginningof THALED® CAPSULE treatment.

These data were provided and analyzed by the Department

Unexpectedly, one of the main reasons of discontinuation ofof Post Marketing Surveillance of Fujimoto Pharmaceutical

THALED® CAPSULE was skin eruption, so that it is important to

Corporation in Osaka. The figures were also made by the same

prevent and/or treat this AE with steroids and antihistamine.

Department. Hirokazu Murakami has received research fund-The other reason of discontinuation of THALED® CAPSULE wasing from Fujimoto Pharmaceutical Corporation in Osaka.

peripheral neuropathy, especially in patients who had previous bortezomib treatment as described above.
We cannot compare the response rates exactly between thissurveillance and the other reports, because there was difference in the response criteria employed and patient’s cohort.
The overall response rate (CR + PR) is lower than previously
reported data 7,15,16). In addition, the combination with othercytotoxic drugs provided the improvement of responsereported by others 17–28), but the overall response rate was not
as good as that in the other reports. One of the reasons of thelower response rate might be the high percentage of patientswith poor PS (PS 3 and 4: 13.3%). The response rate was betterin patients with renal dysfunction. Furthermore, the response
rate of the patients with IgD and light chain myeloma, who areproved to develop renal impairment, was significantly better
than that of other type of myeloma. Based on these data,
thalidomide might be effective for the treatment in thesepatients. However, OS in patients with IgD and light chain subtype was significantly shorter than that of patients in IgG andIgA subtype. Accordingly, it is necessary to develop newtreatment strategy after induction therapy for such patients.
The median DOT, which was almost equivalent to the timeto next treatment, was about 5 months, and satisfactory in thepatients with severe and various disease conditions and poor

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