International Journal of Myeloma 9(2): 1–6, 2019
©Japanese Society of Myeloma

ORIGINAL

Safety of lenalidomide, dexamethasone, and cyclophosphamide
in elderly Japanese patients with relapsed and refractory
multiple m­ yeloma: results of phase 1 study
Yutaka TSUKUNE1, Makoto SASAKI1, Atsushi ISODA2, Jun ANDO1, Michiaki KOIKE3,
Morio MATSUMOTO2, Morio SAWAMURA2, Hideto TAMURA4, Hiroshi HANDA5,
Yoichi IMAI6, Yuriko YAHATA1 and Norio KOMATSU1
The RCd regimen (lenalidomide [LEN]-cyclophosphamide [CY]-dexamethasone [DEX]) was effective and welltolerated in relapsed and refractory multiple myeloma (RRMM) European patients aged between 59 and 65
years. However, most Japanese myeloma patients are over 70 years old. Thus, we analyzed the safety of RCdtherapy in a phase 1 study of elderly Japanese RRMM patients aged >70 years (median age 76 years). CY wasadministered to three cohorts of three patients each at 200, 300, and 400 mg on days 1, 8, and 15 of a 28-day cyclewith DEX (40 mg on days 1, 8, 15, and 22) and LEN (15 mg on days 1–21) for a maximum 8 cycles. One patient
receiving 200 mg CY developed thrombocytopenia (Gr.4) and pneumonia (Gr.3). Two patients each developed
neutropenia (Gr.4) at 300 mg and skin rash (Gr.3) at 200 mg. No severe adverse events were observed. Maximum
tolerated dose of CY was determined to be 400 mg. After 2 cycles, the overall response rate was 88.9%. After amedian follow-up of 36.4 months, median duration of response, progression-free survival, and overall survival
were 8.3, 10.6, and 36.4 months, respectively. (UMIN Clinical Trials Registry number, UMIN000009391).
Key words:

relapsed and refractory multiple myeloma, cyclophosphamide combination therapy, RCd regimen

Introductionthat they produce. Recently, novel agents such as proteasome
inhibitors, immunomodulatory drugs, and monoclonal anti-

Multiple myeloma (MM) is a B-cell neoplasm that causesbodies have been successfully approved, improving prognosis

various symptoms, such as osteolytic bone lesion, anemia, andfor myeloma patients. However, this malignancy is still difficult

renal failure, as a result of the proliferation of monoclonal

to cure outright. Therefore, clinical trials have been conducted

plasma cells in the bone marrow and the increase in M-protein

to investigate the efficacy of new treatment regimens
including these novel agents for relapsed and refractory­

Received February 6, 2019, accepted April 23, 20191
Department of Hematology, Juntendo University School of
Medicine, Tokyo, Japan2
Department of Hematology, National Hospital Organization
Shibukawa Medical Center, Shibukawa, Japan3
Department of Hematology, Juntendo University Shizuoka Hospital,
Shizuoka, Japan
4
Department of Hematology, Nippon Medical School, Tokyo, Japan
5
Department of Hematology, Gunma University Graduate School of
Medicine, Maebashi, Japan
6
Department of Hematology/Oncology, IMSUT Hospital, The Instituteof Medical Science, The University of Tokyo, Tokyo, Japan­multiple myeloma (RRMM).

Corresponding author: Makoto SASAKI, M.D., Ph.D.
Department of Hematology, Juntendo University School of
Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
E-mail: msasaki@juntendo.ac.jp

the National Cancer Center Japan [4]. Due to this discrepancy

Three European groups reported positive outcomes and­tolerable toxicity when treating RRMM with a combination
regimen of lenalidomide (LEN), cyclophosphamide (CY), andsteroids [1–3]. Using such treatment regimens comprising only
oral drugs provide additional advantages in reducing hospital
visits, maintaining existing lifestyles, and allowing patients tocontinue working. The median age in these studies was relatively young (59 to 66 years old) compared to the approximately 65% of patients with MM in Japan who are elderly individuals aged 70 years and older according to the static data ofin the age distribution of the clinical trial patients and the primary target population, these treatment doses and schedules
may not be suitable for treating MM in Japan.

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vol. 9 no. 2 (2019)

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TSUKUNE et al.

Therefore, we planned a phase 1/2 clinical trial to investigate

maximum tolerated dose (MTD) of the RCd regimen, the inci-

the safety and efficacy of RCd therapy (LEN-CY-dexamethasone

dence of adverse events, and the duration of therapy. The[DEX]) in elderly Japanese RRMM patients aged 70 years and­secondary endpoints were the best response rate, duration ofolder, and we herein report the results of the completed phase

response (DoR), progression-free survival (PFS), and overall

1 portion (RefLEX study, UMIN Clinical Trials Registry number,survival (OS). Adverse events were assessed according to the

UMIN000009391).

National Cancer Institute Common Terminology Criteria (NCICTC), version 4.0 after the second cycle of RCd therapy. This

Methods

study used a standard 3 + 3 design to evaluate MTD. If noneof the first three patients developed dose-limiting toxicity

Patients(DLT), a further three patients would be enrolled at the next

The study included Japanese patients aged ≥70 years withdose level. If one or two patients in each dose level developed

symptomatic MM, as diagnosed using the International

DLT, an additional three patients were registered at the same

Myeloma Working Group (IMWG) criteria [5], who had received

level. If only one or two of six patients developed DLT, threeat least one prior treatment regimen. Patients had a Karnofsky

patients were enrolled at the next dose level. If three or more

performance status (KPS) score of greater than 70% or anof six patients had developed DLT, the external safety moni-

Eastern Cooperative Oncology Group (ECOG) performance

toring committee would have reconsidered the continuation­status (PS) of 0–1 (cases of PS 2–3 due to bone lesion or frac-of this study. If treatment-related death occurred, registrationture were allowed to be registered); adequate bone marrow

would be immediately stopped upon submission of a severe9function (defined as platelet count >50 × 10 /L, hemoglobin

adverse event report and the external safety monitoring

concentration >7.0 g/dL, and absolute neutrophil count­committee would discuss the potential discontinuation of

9

1.0 × 10 /L); alanine aminotransferase and aspartate amino-

the study.

transferase ≤2 × the upper limit of normal, and total bilirubin

DLT included: grade 4 hematologic toxicity lasting 7 days

≤2.0 mg/dL; serum creatinine <2.0 mg/dL; adequate cardiac

or more; any non-hematologic toxicity of grade 4 or higher

function (defined as left ventricular ejection fraction ≥50%,

except myeloma and myeloma-treatment associated symp-

and no findings of QT prolongation (<450 ms), atrial fibrillation

toms, such as cataracts, skin lesions, gastritis, diarrhea, hyper-or ­ventricular arrhythmia in electrocardiogram); no abnormal

calcemia, hyperglycemia, polyneuropathy and infections

shadow in both lung fields on the chest X-ray; no severe(including pneumonia); a delay of more than 29 days between

peripheral neuropathy, neuropathic pain and functional loss

courses of RCd therapy due to adverse events; and patient(<grade 2). Furthermore, male patients agree to contraception

refusal due to toxicity. The external safety monitoring com­by one or more appropriate methods during treatment.

mittee assessed the appropriate response according to the

Exclusion criteria included: previous treatment with

International Myeloma Working Group (IMWG) criteria [6].

lenalidomide; complication of systemic amyloidosis; other

Patients were enrolled in 3 dosing cohorts. The dosage

malignancies within 5 years of initiating study treatment;

regimes followed an escalation protocol as shown below: Levelarrhythmia with treatment; history of myocardial infarction,

1: CY 200 mg + LEN 15 mg + DEX 40 mg, Level 2: CY 300 mg +angina pectoris, cerebral infarction or arterial/venous throm-

LEN 15 mg + DEX 40 mg, Level 3: CY 400 mg + LEN 15 mg +bosis; hepatic cirrhosis; requiring hemodialysis; active infec-

DEX 40 mg. CY was orally administered on days 1, 8, 15 (or 22)

tion; infection with human immunodeficiency virus or activeof each 28-day cycle. LEN (15 mg initially, then adjusted

hepatitis B or C virus; severe mental disorders such as

depending on each patient’s renal function) was orally­schizophrenia; or use of major tranquilizer, antidepressant,­administered daily for the first 21 days and DEX was orally

or antimanic drugs.

­administered on days 1, 8, 15, and 22. LEN was discontinued

This study was approved by the institutional review board

if the patient developed grade 3 or 4 peripheral neuropathy

or independent ethics committee at each participating insti-

and skin lesions, as indicated by the package insert. Patientstution and was conducted in accordance with the principles

underwent a maximum of 8 RCd treatment cycles. Patientsfor Good Clinical Practice and the Declaration of Helsinki. All

were allowed to undergo LEN maintenance therapy. Con­patients provided written informed consent.

current thromboembolism prophylaxis was required and prophylaxis for Pneumocystis jirovecii pneumonia and varicella-Study design and treatment

zoster virus infection was recommended. Transfusion and the

The study was designed as a phase 1/2 study and conductedby the Kanto-Tohoku Multiple Myeloma Conference (KTMM)
in Japan. The primary endpoints of the phase 1 trial were the2International Journal of Myeloma

vol. 9 no. 2 (2019)use of granulocyte-colony stimulating factors (G-CSF) werealso allowed, if necessary.

RCd regimen for myeloma in the elderly

Results

Efficacy of RCd
All 9 patients were evaluated for response to treatment with

Patient characteristics

RCd therapy. After 2 cycles of RCd therapy, the overall response

Between January 2013 and December 2015, 10 elderly

rate (ORR) was 88.9% (8 of 9 patients). Eight patients achieved­Japanese patients with RRMM were enrolled in 3 hospitals.

very good partial response (VGPR) or partial response (PR),One patient was subsequently excluded from the study as

including 3 patients with high-risk cytogenetic abnormalities

the dose of LEN for this patient was supposed to be atten­

including t(4;14) and del 17p (Table 1). At the median follow-

uated according to their renal function and the external

up of 36.4 months (range: 21.5–57.5), the median DoR, PFS,

safety monitoring committee concluded that this case wasand OS were 8.3, 10.6, and 36.4 months, respectively.

not suitable for the evaluation of safety. The nine remaining
patients were included in the safety and efficacy analyses.

Discussion

The characteristics and treatment outcomes of patients areshown in Table 1. The median age of the 9 patients (4 males

CY is still a useful and inexpensive agent for myeloma

and 5 females) was 76 (range: 70–80). The median number oftherapy. The safety and efficacy of combination therapies withprior treatment therapies was 2 (range: 1–4). Eight patients

CY and novel agents is well known. In the latest National

had previously received bortezomib-containing regimens and­Comprehensive Cancer Network (NCCN) guidelines (Version

2 patients had received thalidomide-containing regimens. No

2.2019) [7], 4 CY-containing regimens, including PCD

patients had undergone autologous stem cell transplantation.

(pomalidomide-CY-DEX), BCD (bortezomib-CY-DEX), and KCD

Initially, a phase 1/2 study was planned. However, we(carfilzomib-CY-DEX), are recommended as therapy for newly

encountered difficulty in enrolling enough patients to prop-

diagnosed MM (NDMM) or RRMM. The guidelines also recom-

erly evaluate the efficacy of RCd therapy in a phase 2 trial.

mend the RCd regimen as “useful in certain circumstances”

Furthermore, several novel agents that showed favorable­

for primary therapy of non-transplant candidates and is in­treatment outcomes for RRMM were clinically approved after

cluded among “other recommended regimens” for previously

the initiation of this study. Thus, the study was halted follow-

treated MM patients. Although the RCd regimen was first re-ing completion of the phase 1 trial.

ported more than ten years ago, its effectiveness is still being
studied and reported. Of the three RCd therapy studies pre­MTD and safety of RCd

viously reported [1, 2, 8], one was a phase 1/2 study of its use

All 9 evaluated patients received at least 2 cycles of RCdin treatment of RRMM [2]. Patients in this study had a mediantherapy (median: 3 cycles; range: 2–8) and none experienced

age of 65 (range: 42–79) and had undergone a median of 3

DLT at any of the tested dose levels. Adverse events are shown

previous lines of treatment (range: 1–6). Following evaluationin Table 2. At dose level 1 (200 mg CY), one patient (#1-2)

after the first 28-day cycle of RCd, the MTD was fixed at 600 mg

developed pneumonia (grade 3) at day 33 of cycle 1 andof CY administered on days 1 and 8, daily administration of 25

thrombocytopenia (grade 4) at day 18 of cycle 2. This patient

mg of LEN for the first 21 days, and 20 mg of DEX administered

was treated with antibiotic and antifungal agents and recov-

on days 1–4 and 8–11. The MTD for the overall cycle was theered from pneumonia. Thrombocytopenia was improved

same as that found in our study (1,200 mg CY and 160 mg

following discontinuation of LEN. Another patient (#1-3)­

DEX). However, our study used a lower dose of LEN. Eight of­developed skin rash (grade 3) at 200 mg CY and improved

the 31 patients (26%) in the European phase 1/2 trial required­following interruption and dose reduction of LEN. At dosea lower dose of LEN due to adverse events, while only one caselevel 2 (300 mg CY), one patient (#2-1) experienced anemia(#1-3) required dose attenuation in our study.

(grade 3) at day 7 of cycle 2 and neutropenia (grade 4) at day

According to the data of National Cancer Center Japan, the20 of cycle 2. This patient required red blood cell transfusion

number of elderly patients with MM has been significantly

and G-CSF. After 2 cycles, she reached partial response (PR)increasing in Japan [4], so the frailty and comorbidity ofand started LEN maintenance therapy. At dose level 3 (400patients must be taken into consideration during myeloma

mg CY), no patients developed grade 3 or 4 adverse events.

therapy. The European Myeloma Network and IMWG have

The MTD of CY was thus determined to be 400 mg.

­provided scoring systems and dose modification recommen-

Seven of the patients received LEN maintenance therapy

dations for the use of chemotherapeutic agents in frail, elderly

following the RCd regimen. The median duration of therapy ofpatients [9, 10]. For ‘fit’ patients, the doses recommended

RCd and LEN maintenance was 11.6 months (range: 2.1–56.2

were 25 mg of LEN on days 1–21, 300 mg/m2 of CY on days 1,

months). One patient (#2-3) is currently undergoing ongoing

8, and 15, and 40 mg of DEX on days 1, 8, 15, and 22, andLEN maintenance therapy (duration of therapy: 56 weeks).

for ‘unfit’ patients, the recommended doses were 15 mg,

International Journal of Myeloma

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TSUKUNE et al.

Table 1.

Baseline characteristics and therapeutic outcomes of patients treated with the RCd regimen
Dose level 1

Patient number

#1-1

#1-2

#1-3

Age/Gender

70/male79/female

74/maleECOG PS000Geriatric assessment*

Fit

Unfit

Fit

M-protein

IgG-λ

IgG-λ

IgG-κ

DSS/ISS

IIIA/II

IIA/I

IIIA/II

Cytogenetic abnormalitiest(4;14)**Not(4;14)**, Hyperdiploidy

Previous lines of treatment

1

2

1

Prior treatment (cycles)

BD (11), MPB (5)BD (8) and bortezomib
maintenance, MPB (8)BD (7)

RCd cycles

8

3

8

LEN maintenance (Dose)Yes (10 mg daily)

Yes (10 mg daily)

Yes (10 mg daily)

Adverse events

No

Pneumonia (G3)
Thrombocytopenia (G4)Skin rash (G3)Best response

PR

PR

PR

Dose level 2
Patient number

#2-1

#2-2

#2-3

Age/Gender

80/female

76/female

80/female

ECOG PS1

3 (bone lesion)

0

Geriatric assessment*

Unfit

Frail

Unfit

M-protein

IgA-κ

IgG-κ

IgG-κ

DSS/ISS

IIIA/III

IIIA/II

IIA/II

Cytogenetic abnormalities

Del 17p**, t(4;14)**NoNo

Previous lines of treatment

3

2

2

Prior treatment (cycles)

MP (1), BD (5),BD re-treatment (5)MP (4) and thalidomide
maintenance, MPB (4)HDD, MPT (7) and thalidomide
maintenance

RCd cycles

2

2

5

LEN maintenance (Dose)Yes (10 mg)

No

Yes (5 mg) ***Adverse events

Anemia (G3), Neutropenia (G4)

Neutropenia (G1), Pharyngitis (G1)

Peripheral neuropathy (G2)Best response

PR

PR

VGPR

Dose level 3
Patient number

#3-1

#3-2

#3-3

Age/Gender

73/female

73/male76/maleECOG PS

1

1

0

Geriatric assessment*

Fit

Fit

Unfit

M-protein

LC-λ

LC-λ

IgA-κ

DSS/ISS

IIIA/III

IIIB/III

IIIB/III

Cytogenetic abnormalities

No

No

No

Previous lines of treatment

2

1

4

Prior treatment (cycles)

ROAD (8), BD (10)BD (4) and bortezomib
maintenance

VAD (4), MP (15), BD (7),BD re-treatmment (10)

RCd cycles

2

2

4

LEN maintenance (Dose)No

Yes (10 mg)

Yes (5 mg)

Adverse events

Peripheral neuropathy (G2)Upper respiratory infection (G2)No

NoBest response

SD

PR

PR

*patients were classified as ‘Fit’, ‘Unfit’, or ‘Frail’ according to the IMWG proposed scoring system [10].
**fluorescent in situ hybridization (FISH) analysis.
***ongoing.
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; DSS, Durie and Salmon staging system; ISS, International
Staging System; LEN, lenalidomide; LC, light chain; BD, bortezomib and dexamethasone; MPB, melphalan, prednisolone, and bortezomib; MP,melphalan and prednisolone; HDD, high-dose dexamethasone; MPT, melphalan, prednisolone, and thalidomide; ROAD, ranimustine, vincristine,
melphalan, and dexamethasone; VAD, vincristine, doxorubicin, and dexamethasone; PR, partial response; VGPR, very good partial response; SD,
stable disease.

4International Journal of Myeloma

vol. 9 no. 2 (2019)RCd regimen for myeloma in the elderly

Table 2. Adverse events observed in patients treated with the RCd
regimentoxicity,’ referring to the increased financial burden associ-Adverse event, n (%)

All grade

Grade 3/4

quality of life, has become recognized as a global issue [13].

Anemia1 (11.1)

1 (11.1)

Although several public medical health insurance systems

Thrombocytopenia

1 (11.1)

1 (11.1)

cover almost all Japanese people, some patients with colorec-

Neutropenia

2 (22.2)

1 (11.1)

tal cancer have been unable to receive the most appropriate

Peripheral neuropathy

2 (22.2)0  (0.0)

treatment due to economic reasons [14]. In general, the cost-

Skin rash

1 (11.1)

1 (11.1)

effectiveness of drugs and treatment should be evaluatedPharyngitis

1 (11.1)0  (0.0)

using the quality-adjusted life-year (QALY) and incremental

Upper respiratory infection

1 (11.1)

1 (11.1)

cost-effectiveness ratio (ICER). A recent study showed that the

Pneumonia

1 (11.1)

1 (11.1)

IRD regimen had a higher ICER than other novel agent-based

ated with cancer treatment that adversely affects a patient’s

regimens for the treatment of MM [15]. As we did not evaluate the QOL and cost of the therapy, it was impossible to
150 mg/m2, and 20 mg. The MTDs of RCd therapy in our study­analyze the cost-effectiveness of our RCd regimen. However,were approximately equal to these recommended doses

because of the low price of CY, its use in combination regimens

and are therefore considered to be appropriate for elderly

does not significantly increase the cost of these therapies.

­Japanese patients with RRMM.

Thus, the RCd regimen may be a viable option for affordable

The RCd regimen is composed entirely of orally adminis-

treatment of RRMM.

tered drugs, which reduces frequency of hospital visits and

All things considered, we think that RCd therapy is a safe

duration of hospital stay. This is a major benefit for patientsand reasonable option for the treatment of elderly Japanesewith bone disease, disability, and comorbidity, and who live far

RRMM patients.

from hospitals. Additionally, triplet combinations have been

Acknowledgments

recommended for patients with RRMM, because they haveproduced more favorable outcomes than doublet regimens[11]. The NCCN guidelines proposed 33 treatment regimens

The authors would like to thank Dr. Yoshihiro Hatta (Nihon

for RRMM [7]. Of these, two triplet combination therapies

University School of Medicine), Dr. Takamitsu Okamura­consisting only of orally administered drugs are approved in(­Dokkyo Medical University Saitama Medical Center), and Dr.

Japan: the IRD (ixazomib [IXA]-LEN-DEX), and RCd therapies.

Tsuyoshi Takahashi (Mitsui Memorial Hospital) for their review

The efficacy of IRD was evaluated in a phase 3 TOURMALINE-of the clinical data as members of the external safety moni­

MM1 trial [12]. The median age and previous lines of treatment

toring committee.

undergone by patients were 66 (range: 38–91) and 1 (range:
1–3), respectively. The ORR was 78% and 2-year PFS was

Conflict of Interest

around 50%. Any and grade 3 or 4 adverse events wereobserved in 98% and 74% of patients, respectively. In the pre-

Makoto Sasaki received honoraria for lectures from Celgene,viously described phase 1/2 RCd study [2], the ORR was 81%

Takeda Pharmaceutical, and Janssen. Hideto Tamura discloses

and 2-year PFS was 56%. Grade 3 or 4 complications occurred

receipts of honoraria for lectures from Bristol-Myers Squibb,

in 19% of patients. Comparing patient characteristics in these

Celgene, Ono Pharmaceutical, Takeda Pharmaceutical, and2 studies, age was consistent, while the number of previous

research grant from Celgene. Hiroshi Handa received hono-lines of regimens was larger in the RCd group than in the IRD

raria and research grant from Celgene. Norio Komatsu hasgroup. Based on these outcomes, it seems that the RCd

received a consulting fee from Celgene. The remaining authors­regimen has a lower incidence and lower grade of adverse

declare that they have no conflicts of interest.

events than IRD therapy. Additionally, the MTD of our study
is lower than that reported in a previous RCd study. Thus, ourReferences

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