□ CASE REPORT □Peripheral Neuropathy Exacerbated by Lenalidomide
in a Patient with Multiple Myeloma
Tomohiko Kamimura 1, Toshihiro Miyamoto 2, Noriko Yokota 3,
Takatoshi Aoki 1, Yoshikiyo Ito 1 and Koichi Akashi 2

Abstract
We evaluated a serial change in peripheral neuropathy (PN) severity during treatment with bortezomib(Bor) or lenalidomide (Len) using the Functional Assessment of Cancer Therapy scale/Gynecologic Oncology
Group-Neurotoxicity (FACT/GOG-Ntx). The patient suffered from grade 2 PN and exhibited a dramatic decrease in FACT/GOG-Ntx score after intravenous and subcutaneous Bor therapy. Thereafter, he received
seven cycles of Len therapy, which exacerbated existing PN; he experienced mild numbness and exhibited atransient decrease in FACT/GOG-Ntx score. Interestingly, FACT/GOG-Ntx score increased to baseline andnumbness was ameliorated during the Len washout period in every cycle.
Key words: multiple myeloma, peripheral neuropathy, lenalidomide, FACT/GOG-Ntx(Intern Med 53: 1651-1653, 2014)(DOI: 10.2169/internalmedicine.53.1354)

Introduction

Case Report

Lenalidomide (Len) is a second-generation thalidomide
analog that has become a cornerstone treatment for multiple
myeloma (MM), particularly for patients with relapses or refractory disease. Two prospective randomized studies demonstrated that there was no increase in clinically significant
peripheral neuropathy (PN) in relapsed MM patients treatedwith Len compared with those treated with dexamethasone (1, 2). These studies indicate that unlike bortezomib(Bor) or thalidomide, Len is expected to rarely induce or exacerbate PN (1, 2). Therefore, it has been suggested thatLen can be safely administered to patients with existing PN
or a history of PN. Although clinicians are aware that Len
occasionally aggravates existing PN (3, 4), particularly during early treatment cycles (4), there is little detailed information regarding the clinical course of PN following treatment with Len (i.e., whether Len-induced PN is reversible).
We herein describe the detailed clinical course of Borinduced PN that was transiently, but reversibly, exacerbatedfollowing salvage Len administration in a patient with relapsed MM.

In April 2009, a 56-year-old Japanese man presented withpathologic vertebral fractures and multiple osteolytic lesions;
he was subsequently diagnosed with MM with Bence-Jones
protein κ [International Staging System (ISS) Stage 2,
Durie-Salmon stage IIIB] and exhibited a normal karyotype
and 30% plasma cells on bone marrow (BM) assessment.
The patient received one cycle of combination vincristine,
doxorubicin, and dexamethasone (VAD) chemotherapy, followed by intravenous Bor and dexamethasone therapy twice
weekly (ivBD; Bor, 1.3 mg/m2; dexamethasone, 40 mg) on
days 1, 4, 8, and 11, and thereafter every 3 weeks. Although
there was a partial response (PR) to the first cycle, ivBD
was discontinued because of the patient developed grade 3
PN, which left him unable to walk without support. Subsequently, the patient received two autologous peripheral
blood stem cell transplants (ASCTs), resulting in very goodPR. However, he relapsed 15 months after the second ASCTand experienced severe bone pain. BM assessment revealed
9.6% plasma cells. Based on his rapid response to ivBD, he
was treated with subcutaneous (sc) BD salvage therapy once

１

Department of Hematology, Harasanshin Hospital, Japan, ２Department of Medicine and Biosystemic Science, Graduate School of Medical Science, Kyushu University, Japan and ３Department of Nursing, Harasanshin Hospital, Japan
Received for publication August 17, 2013; Accepted for publication January 26, 2014
Correspondence to Dr. Toshihiro Miyamoto, toshmiya@intmed1.med.kyushu-u.ac.jp1651

Intern Med 53: 1651-1653, 2014

DOI: 10.2169/internalmedicine.53.1354(a) Serial change in FACT/GOG-Ntx scores during bortezomib therapy
35

FACT/GOG Ntx

30

1st cycle
2nd cycle

25

3rd cycle
4th cycle

20

5th cycle
6th cycle

15

7th cycle

10
day 1

day 8

day 15day 22day 28Treatment day of each cycle(b) Serial change in FACT/GOG-Ntx scores during lenalidomide therapy
35

FACT/GOG Ntx

30

1st cycle
2nd cycle

25

3rd cycle
4th cycle

20

5th cycle
6th cycle

15

7th cycle

10
day 1

day 8

day 15day 22Treatment day of each cycle

Figure. Serial changes in FACT/GOG-Ntx during (a) scBD
therapy and (b) LD therapy. (a) The FACT/GOG-Ntx score decreased from 35 on day 1 of the first cycle to 15 on day 8 of the
fourth cycle, resulting in reduction of Bor from 1.3 mg/m2 to
1.0 mg/m2. Thereafter, the FACT/GOG-Ntx score varied between 15 and 29 without further decrease. (b) The FACT/GOG-Ntx score was 23 at the start of LD therapy due to Borinduced PN before Len treatment. The score transiently decreased on days 8, 15, and 22 but recovered to baseline by thestart of the next LD treatment cycle.

weekly (Bor, 1.3 mg/m2; dexamethasone, 40 mg) on days 1,
8, 15, and 22 every 4 weeks, and his PN reduced to grade
1. PN symptoms were scored weekly using the Functional
Assessment of Cancer Therapy scale/Gynecologic Oncology
Group-Neurotoxicity (FACT/GOG-Ntx) (5), which is comprised of 11 questions rated on a 5-point scale from 0 (“notat all”) to 4 (“very much”). An increased total score ranging
from 0 to 44 was classified as “improved,” whereas unchanged or declining scores was classified as stable/declined (5). The first cycle of scBD significantly decreased
his bone pain and reduced the number of plasma cells to
1.6% on BM assessment. After the second cycle of scBD,
he reported a mild increase in limb numbness. Figure ashows the serial change in his FACT/GOC-Ntx scores overtime. Although the score decreased from 35 to 25 by theend of the second scBD cycle and his PN was still categorized as grade 1 with mildly worsened numbness and tolerable, the treatment was continued without a reduction in Bor

because of the significant efficacy of the treatment. However, on day 8 of the fourth cycle of scBD, his FACT/GOGNtx score decreased to 15, and his PN exacerbated to grade
2 with aggravation of limb numbness; therefore, Bor was reduced from 1.3 mg/m2 to 1.0 mg/m2 (Figure a). The FACT/GOG-Ntx score transiently increased from 15 to 29 on day
1 of the fifth cycle with improvement of limb numbness.
However, in January 2012, after seven cycles of scBD, the
FACT/GOG-Ntx score decreased to 19 on day 28 of theseventh cycle. We found that the patient’s MM had progressed with back pain and elevation of serum κ-free lightchain (serum κ-FLC, 2,610 mg/L; λ-FLC, 6.1 mg/L; κ/λ ratio, 427.9). When we compared the mean FACT GOG-Ntx
score in the first cycle of scBD treatment with those during
subsequent cycles using Tukey’s test, the mean of the scorein the first cycle (32.0±1.9) was comparable with the meanscore in the second cycle (28.6±3.0). However, the means ofscores in the third (20.8±1.6), fourth (21.6±3.9), fifth (24.6±
2.6), sixth (19.2±2.5), and seventh cycles (23.6±1.2) weresignificantly lower than the mean score in the first cycle (p<0.01). Next, we compared the mean FACT GOG-Ntx score
on day 1 with the mean scores on other days during allseven scBD treatment cycles using a Mann-Whitney U-test.
There were no significant differences between day 1 andother days. These results demonstrate that existing PN was
exacerbated by scBor treatment and was never restored tothe baseline by the start of the next scBD treatment.
Subsequently, the patient started Len and dexamethasone
therapy every 28 days (LD; Len, 10 mg for 14 days; dexamethasone, 40 mg, daily on days 1, 8, 15, and 22) becauseof renal dysfunction and persistent grade 2 thrombocytopenia and neutropenia. After the first LD cycle, his backpain disappeared, and κ-FLC dramatically decreased (κFLC, 155 mg/L; λ-FLC, 7.4 mg/L; κ/λ ratio, 20.9). He received seven cycles of LD until disease progression without
requiring reduction of Len dosage. His PN was transiently
exacerbated with mild worsening of limb numbness for several days after the beginning of each LD cycle, but his
symptoms improved during the Len washout period of 14days in each cycle. Figure b shows the serial change in
FACT GOG-Ntx scores during the seven LD treatment cycles. At the start of treatment, his baseline score was 23, andgrade 2 PN was present from the previous ivBor and scBor
treatments. In the first LD treatment cycle, the FACT/GOGNtx score decreased from 23 on day 1 to 19 on day 15.
Thereafter, the score increased to 26 on day 1 of the second
cycle, and the score at day 1 was maintained at 26 as thebaseline in subsequent cycles. Similar to the kinetics of the
FACT/GOG-Ntx score in the first cycle, the score decreased
from 26 on day 1 to 20 on day 22 in the third cycle; 22 on
day 8 in the fourth cycle; and 24 on day 8 in the fifth, sixthand seventh cycles. When we compared the mean FACTGOG-Ntx score in the first cycle with those in subsequent
cycles using Tukey’s test, the mean FACT/GOG-Ntx scorein the first cycle (21.5±1.9) was comparable with those in
the third (23.5±2.5), fourth (24.5±1.9), sixth (25±1.2) and1652

Intern Med 53: 1651-1653, 2014

DOI: 10.2169/internalmedicine.53.1354

seventh cycles (25±1.2), whereas the means of the scores inthe second (25.5±1.0, p<0.05) and fifth cycles (25.5±1.9, p<0.05) were significantly higher than the mean of score in thefirst cycle (21.5±1.9). These results indicated that the meansof FACT/GOG-Ntx scores did not decrease following repeated LD treatments. In addition, the mean FACT GOGNtx score on day 1 (just before the start of each LD treatment cycle) was significantly higher than that of other days
(25.0±1.0 vs. 23.9±2.1, p=0.046) (Mann Whitney U-test).
These results indicated that FACT GOG-Ntx scores decreased with LD treatment on days 8, 15, and 22 but returned to baseline by the start of the next LD cycle. In August 2013, his MM relapsed and rapidly progressed. The patient underwent allogeneic bone marrow transplantationfrom a related donor following a reduced-intensity conditioning regimen consisting of melphalan (140 mg/m2), fludarabine (150 mg/m2), and total body irradiation (4 Gy), but
he subsequently succumbed to sepsis and multiple organ
failure 15 days after transplantation.

did not seem to improve in the short-term observation during scBD treatment, slowly improved after cessation of
scBD treatment in the long term, even during LD treatment.
Therefore, the means of FACT/GOC-Ntx scores increased insome LD treatment cycles compared to the mean score in
the first cycle, although administration of Len mildly andtransiently exacerbated PN in each treatment cycle. Although the efficacy of the FACT/GOG-Ntx for evaluating
Bor-induced PN is known (7), this report is the first toevaluate PN exacerbation after Len administration. Based on
our experience with this patient, physicians should be awarethat any exacerbation of existing PN due to Len administration may be reversible and thus will likely improve during
the washout period. A large prospective study is required tofurther assess the efficacy of the FACT/GOG-Ntx to evaluate PN following Len administration, as well as the reversibility of PN exacerbation by Len.

Discussion

Acknowledgement
We thank the nursing staff who cared for the patient at theHarasanshin Hospital for providing the patient’s information.

One cycle of ivBor induced intolerable severe PN that required treatment cessation, whereas scBor was continued forseven cycles with only mild progression of existing PN.
This clinical course was consistent with that of a previous
report describing that scBor was associated with decreased
PN incidence and severity with equivalent efficacy to
ivBD (6). However, our patient’s FACT/GOG-Ntx score decreased from 35 to 19 by the end of scBor treatment (Figure a) and was 23 at the start of Len (Figure b). Statistically, despite the reduction of Bor after the fourth cycle of
scBD treatment, the means of the FACT/GOG-Ntx scores inthe second and subsequent cycles became significantly lower
than the mean score in the first cycle (p<0.01). In contrast
to Bor, although Len exacerbated existing PN, this was only
temporary because PN recovered to baseline severity by thetime of the next LD cycle. Particularly, the mean FACTGOG-Ntx score on day 1 was significantly higher than thatof other days (25.0±1.0 vs. 23.9±2.1, p=0.046). Interestingly, reversibility of PN exacerbation due to Len was
clearly evidenced by both the patient’s reports of limb
numbness and changes in the FACT GOG-Ntx score. In addition, although the FACT/GOG-Ntx score transiently decreased in every treatment cycle, the means of the scores of
the third, fourth, sixth, and seventh LD treatment cycles
were significantly higher than the mean score of the first cycle. These results might indicate that Bor-induced PN, which

The authors state that they have no Conflict of Interest (COI).

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