post-marketing surveillance of the treatment with … · 8 international journal of myeloma vol. 5...

International Journal of Myeloma vol. 5 no. 1 (2015)8

Post-marketing surveillance of the treatment with THALED® CAPSULE in patients with relapsed/refractory multiple myeloma

Hirokazu MURAKAMI1, Kazuyuki SHIMIZU2 and Toshiyuki TAKAGI3

THALED® 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 post-

marketing surveillance was necessary and was conducted accordingly. This study included 1,548 patients during a

period 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 a

dosage below 200 mg/day. All grade and serious adverse events (AEs) were observed in 58.6% and 8.7%, respec-

tively. The incidence of these AEs was lower than that observed in the previous domestic clinical study; however the

monitoring 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 used

safely in clinical practice of Japanese MM patients.

Key words: myeloma, thalidomide, adverse event, venous thromboembolism, peripheral neuropathy

Introduction

Multiple myeloma is a clonal plasma cell disorder account-

ing for 10% of hematological malignancies. Melphalan plus

prednisone treatment has been the mainstay of myeloma

treatment since the 1960s. Approximately 50% of patients

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

ble and the median overall survival (OS) was only three years 1).

The median OS has now been improved by high-dose

chemotherapy with autologous stem cell transplantation 2).

Additionally, novel agents including immunomodulatory drugs

(thalidomide and lenalidomide) and proteasome inhibitor

(bortezomib) have provided further improvement in the out-

come of myeloma treatment 3).

Thalidomide was introduced to the market in the 1950s as

a sedative. However, Lenz 4) disclosed a close relationship

between the exposure to thalidomide in pregnant women

and the development of phocomelia (flipper-like limb) in their

neonates in 1961. In 1994, D’Amato et al. 5,6) showed that

thalidomide inhibited angiogenesis in the experiments using

rabbits and suggested thalidomide as a possible therapeutic

agent for diseases that show increased angiogenesis, particu-

larly for malignant tumors. After the report, clinical trials with

thalidomide were initiated in many countries testing the

possibility as a new therapeutic agent for multiple myeloma

(MM) patients, and the effectiveness of thalidomide is now

well established in not only relapsed/refractory but also newly

diagnosed patients 7,8).

THALED® CAPSULE (thalidomide) was approved as a drug

for relapsed/refractory MM in October 2008 in Japan. Because

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 end

of December 2013.

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

Received: October 6, 2014, accepted: November 8, 20141Gunma University Graduate School of Health Sciences2Tokaichuo Hospital3Kimitsu Chuou Hospital

Corresponding author: Hirokazu MURAKAMIGunma University Graduate School of Health Sciences, 3-39-15 Showa-machi, Maebashi, Gunma, JapanTEL & FAX: +81-27-220-8973E-mail: [email protected]

9International Journal of Myeloma vol. 5 no. 1 (2015)

Post-marketing surveillance of THALED® CAPSULE

Patients and Methods

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

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

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

Patients were followed until discontinuation of the treatment,

otherwise up to 104th weeks.

Toxicities were graded according to the Article 253 of the

Pharmaceutical Affaires Law Enforcement Regulations.

The responses obtained by 16th weeks from the start of

THALED® CAPSULE treatment were assessed by the maximum

decrement of monoclonal protein (M-protein) and are defined

as: complete response (CR); negative immunofixation of the

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

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

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

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

detectable M-protein, the response was assessed by the size

of plasmacytoma and bone marrow plasmacytosis. Duration

of treatment (DOT) was measured from the date of initiation

of THALED® CAPSULE treatment until death or discontinuation

of the treatment, whichever happened earlier. Overall survival

(OS) was measured from the date of initiation of THALED®

CAPSULE treatment until death or last seen, whichever came

earlier.

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 was

assessed using either t-test (age), χ2-test (immunoglobulin

subtype, performance status (PS) and previous treatment

regimens), Wilcoxon (disease duration) or Fisher’s exact

test (gender, renal and liver dysfunction). Cochran-Mantel-

Haenszel test was used to examine the difference of the inci-

dence 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 the

incidence of VTE in patients either with or without the use of

prophylactic agents. Effectiveness was also assessed using

either t-test or Wilcoxon, and χ2-test or Fisher’s exact test was

used as safety assessment. The DOT and OS curves were

constructed according to the Kaplan-Meier method, and differ-

ences between the survival curves were tested for statistical

significance using the log-rank test.

This study was supported for data collection and statistical

analysis by Fujimoto Pharmaceutical Corporation in Osaka,

and the authors evaluated the safety and effectiveness of

THALED® CAPSULE.

Results

Patient characteristics

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

All patients were diagnosed as refractory/relapsed MM. The

median age was 69.0 years (range: 33–93 years), and male/

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

duration from the initial diagnosis was 2.9 years (range: 0–25

years). About 20% of the patients had relapsed after high-dose

chemotherapy with autologous stem cell transplantation. The

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

624 (40.3%), 303 (19.6%), 161 (10.4%), and 45 (2.9%) patients,

respectively.

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

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

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

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

of the last visit. Almost all patients (98.5%) were treated at a

dosage below 200 mg/day.

Adverse events

The toxicity profile observed in at least 3% of patients is

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

Table 1. Patient characteristics

Gender (male/female) 787/761Age (mean ± SD) years 68.5 ± 10.0Disease duration (mean ± SD) years 3.8 ± 3.4Ig isotype

IgG (%) 919 (59.4)IgA (%) 336 (21.7)IgD (%) 46 (3.0)IgE (%) 1 (0.1)IgM (%) 8 (0.5)Light-chain myeloma (%) 187 (12.1)Non-secretary (%) 49 (3.2)unknown (%) 2 (0.1)

Performance status0/1/2/3/4/unknown(%)

413/624/303/161/45/2(26.7/40.3/19.6/10.4/2.9/0.1)

Renal dysfunction*+/– (%) 307/1,241 (19.8/80.2)

Liver dysfunction*+/– (%) 87/1,461 (5.6/94.4)

Past treatmentASCT (%) 348 (22.5)1 regimen (%) 404 (26.1)2 regimen (%) 336 (21.7)3 regimen (%) 240 (15.5)>4 regimen (%) 178 (11.5)unknown (%) 42 (2.7)

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


MURAKAMI et al.

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

patients, respectively. The incidence of these AEs was lower

than that observed in the domestic clinical study (phase I/II),

although it was higher in patients having a longer duration

of the disease in this study (p = 0.0166). However, there

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

(p = 0.5604), previous treatment regimens (p = 0.8845), or

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

(p = 0.5756). Surprisingly, the incidence of AEs was significant-

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

patients could not continue THALED® CAPSULE treatment,

and accordingly had a significantly shorter duration of treat-

ment. This shorter treatment duration might have contributed

to the low incidence of AEs.

The predominant AEs were peripheral neuropathy (17.1%),

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

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

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

of hematological toxicities, including leukopenia, thrombocy-

topenia, and neutropenia, kept increasing until the 12th weeks

from the start of THALED® CAPSULE treatment and became

plateau thereafter. Compared with the domestic clinical study,

the incidence of neutropenia in this study was extremely low,

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

According to the reduction rate of neutrophil listed in NCI-CTC

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

of Grade 1 and 3 were 69.8% and 27.0%, respectively. Venous

thromboembolism (VTE) and serious VTE were observed in 22

cases (1.4%) and 13 cases (0.8%), respectively. There was no

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

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

tion with steroids (p = 0.8966)/chemotherapy (p = 0.6699), and

the presence of the complication of diabetes mellitus (p =

0.9238) and infection (p = 0.5068). The incidence was signifi-

cantly higher in patients with previous history of cardiac

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

incidence regardless of the adaptation of prophylaxis with

aspirin (p = 0.8116). Peripheral neuropathy kept increasing

until the 17th weeks from the start of THALED® CAPSULE treat-

ment 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 experi-

enced eruption and one-fourth of patients who experienced

peripheral neuropathy discontinued thalidomide treatment.

The incidence of constipation was high, however discontinua-

tion rate was low (1/10).

Table 2. Toxicity profile observed over 3% of patients

Toxicity Non-severe (%) Severe (%) Total (%)

Hematological toxicityLeukopenia 98 (6.3) 20 (1.3) 118 (7.6)Thrombocytopenia 81 (5.2) 7 (0.5) 88 (5.7)Neutropenia 46 (3.0) 10 (0.6) 56 (3.6)Anemia 42 (2.7) 5 (0.3) 47 (3.0)

Non-hematological toxicityPeripheral neuropathy 255 (16.5) 10 (0.6) 265 (17.1)Constipation 189 (12.2) 2 (0.1) 191 (12.3)Somnolence 118 (7.6) 1 (0.1) 119 (7.7)Dizziness 107 (6.9) 1 (0.1) 108 (7.0)Skin eruption 103 (6.7) 1 (0.1) 104 (6.7)Increase of CRP 65 (4.2) 6 (0.4) 71 (4.6)Fatigue 47 (3.0) 2 (0.1) 49 (3.2)

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



Response rate, duration of treatment and overall survival

Fifteen patients (1.3%), 263 patients (22.0%), and 273 patients

(22.8%) achieved CR, PR and MR, respectively. The response

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

above MR was significantly higher in patients with IgD type

and light chain myeloma (p = 0.0003).

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 treated

with THALED® CAPSULE alone (37.3%) (p < 0.0001).

Median OS was not reached, and the 1-year and 2-year OS

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%,

respectively (Fig. 2).

There were significant differences in OS and DOT in regard

to PS and renal function (Fig. 3A–D). The 2-year OS in patients

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

25.5%, respectively (p < 0.0001). The 2-year DOT in patients

with PS 0, 1, 2, and 3 plus 4 were 15.8%, 11.7%, 6.6%, and 1.7%,

respectively (p < 0.0001). The 2-year OS in patients with and

without renal dysfunction were 56.7% and 74.3%, respectively

(p < 0.0001). The 2-year DOT in patients with and without renal

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

There was significant difference in OS according to immuno-

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

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).

Discussion

Between February 2009 and February 2010, 1,548 patients

were enrolled in this post-marketing surveillance of THALED®

CAPSULE. It was found that almost all patients were treated

with thalidomide below 200 mg/day. In the initial phase of

clinical trial of thalidomide, high dose thalidomide up to 800

mg/day was recommended 7), however the efficacy and safety

of low-dose thalidomide is now well established 9,10). In the

Japanese 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 than

in the previous domestic clinical study, was probably due to

the difference of toxicity criteria and dose of thalidomide. In

addition, the monitoring and audit was not performed in this

surveillance, 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 incidence

of Grade 3/4 neutropenia, so that neutropenia should have

Table 3. Drugs combined with THALED® CAPSULE

Drug No. of patients (%)

dexamethasone 397 (25.6)prednisolone 354 (22.9)melphalan 207 (13.4)bortezomib 38 (2.5)cyclophosphamide 36 (2.3)doxorubicin 11 (0.7)vincristine 10 (0.6)methylprednisolone 8 (0.5)others 16 (1.0)

Figure 2. Overall survival (OS) and duration of treatment (DOT) of all patients treated with THALED® CAPSULE.


MURAKAMI et al.

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



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

of VTE in this surveillance was apparently lower compared

with the reports from U.S.A and Europe, and had been already

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

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

index, combination with steroids/chemotherapy, diabetes

mellitus, and infection, could not predict the development of

VTE. Prophylactic efficacy of aspirin for VTE was not observed

in this surveillance; however it is necessary to perform a pro-

spective study. Five patients had pulmonary embolism, and

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

most serious AEs. Long-term administration of thalidomide

and previous bortezomib treatment seem to contribute to

peripheral neuropathy, accordingly a careful assessment of

neurological complaints is required in these patients. The inci-

dence of hematological toxicities, especially neutropenia,

increased up to the 12th weeks and became plateau there-

after. According to this data, it is necessary to check frequently

the complete blood count until 3 months from the beginning

of THALED® CAPSULE treatment.

Unexpectedly, one of the main reasons of discontinuation of

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

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

The other reason of discontinuation of THALED® CAPSULE was

peripheral neuropathy, especially in patients who had previ-

ous bortezomib treatment as described above.

We cannot compare the response rates exactly between this

surveillance and the other reports, because there was differ-

ence 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 other

cytotoxic drugs provided the improvement of response

reported by others 17–28), but the overall response rate was not

as good as that in the other reports. One of the reasons of the

lower response rate might be the high percentage of patients

with poor PS (PS 3 and 4: 13.3%). The response rate was better

in patients with renal dysfunction. Furthermore, the response

rate of the patients with IgD and light chain myeloma, who are

proved 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 these

patients. However, OS in patients with IgD and light chain sub-

type was significantly shorter than that of patients in IgG and

IgA subtype. Accordingly, it is necessary to develop new

treatment strategy after induction therapy for such patients.

The median DOT, which was almost equivalent to the time

to next treatment, was about 5 months, and satisfactory in the

patients with severe and various disease conditions and poor

PS. However, the OS in this surveillance, which did not reach to

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

quent salvage treatments with other novel agents.

Conclusion

It is difficult to compare the present data in the other clinical

data reported from U.S.A. and Europe because this study is

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

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

and Europe, so that THALED® CAPSULE can be used safely in

clinical practice of Japanese MM patients.

Acknowledgment

We thank all patients and medical staff members in attend-

ing institutions who have agreed to participate in this surveil-

lance study.

Conflict of Interest

These data were provided and analyzed by the Department

of Post Marketing Surveillance of Fujimoto Pharmaceutical

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

Department. Hirokazu Murakami has received research fund-

ing from Fujimoto Pharmaceutical Corporation in Osaka.

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