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Kunacheewa et al.

Chutima Kunacheewa, M.D., Noppadol Siritanaratkul, M.D.

Department of Medicine, Faculty of Medicine Siriraj Hospital, Bangkok 10700, ailand.

Efcacy of Lenalidomide plus Low-Dose

Dexamethasone in Thai Patients with Relapsed

and/or Refractory Multiple Myeloma

ABSTRACT

Objective: Lenalidomide is an immunomodulatory agent with proven ecacy in the treatment of multiple myeloma.

In large global clinical studies, lenalidomide plus dexamethasone has demonstrated signicant improvements in the

overall response rate and overall survival in patients with relapsed and/or refractory multiple myeloma, compared

with a placebo and dexamethasone. is is the rst study to report lenalidomide plus low-dose dexamethasone

administered in ai patients.

Methods: e aim of this phase II, single-center, single-arm study was to evaluate the ecacy and safety of

lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. e

primary endpoint was the overall response rate at the fourth treatment cycle. Secondary endpoints included depth

of response, time to response, and adverse events.

Results: In total, 15 patients with a median age of 61 years old (range 23-74 years old) who had received at least

one prior anti-myeloma therapy were enrolled in the study and administered 4-week cycles of lenalidomide 25

mg/day (days 1-21) and dexamethasone 40 mg/week. Patients continued in the study until the occurrence of

disease progression or serious adverse events. e overall response rate was 86% and 73.3% at the fourth and from

all treatment cycles, respectively (median number of treatment cycles, 10.25), and the median dose for patients

aged >60 years old was 15 mg/day. e overall response rate at the fourth cycle in patients who had received prior

novel agents (bortezomib and/or thalidomide) was 81.82% compared with 100% in those who had received prior

conventional therapy (p = 0.15). e most common adverse events reported were anemia and neutropenia, which

were both manageable.

Conclusion: Lenalidomide and low-dose dexamethasone was highly eective in ai patients with relapsed and/

or refractory multiple myeloma, with a manageable adverse event prole. ese ndings suggest that lenalidomide

15 mg/day is a safe and eective dose for ai patients aged ≥60 years old.

Keywords: Relapsed multiple myeloma; refractory multiple myeloma; lenalidomide; adverse events (Siriraj Med J

2021; 73: 344-353)

Corresponding Author: Noppadol Siritanaratkul

E-mail: sinoppadol@gmail.com

Received 29 May 2020 Revised 4 January 2021 Accepted 6 January 2021

ORCID ID: http://orcid.org/0000-0001-8624-5516

http://dx.doi.org/10.33192/Smj.2021.45

INTRODUCTION

Multiple myeloma is a plasma cell disorder that,

to date, remains incurable.

Patients with relapsed and

treatment-refractory multiple myeloma require eective

salvage therapies to prolong disease-free progression.

e introduction of autologous stem cell transplantation,

and newer agents for the treatment of multiple myeloma,

has substantially improved the options available for

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patients who do not respond well to initial therapy. Novel

agents including immunomodulatory drugs (thalidomide,

lenalidomide), proteasome inhibitors (bortezomib,

carlzomib, and ixazomib), and monoclonal antibodies

(elotuzumab and daratumumab) in combination with

other agents have all demonstrated favorable results in

terms of response, progression-free survival, and also

overall survival, compared to established treatments for

refractory disease, such as melphalan-based regimens or

alkylating agents.

1-4

Currently, worldwide practice uses a combination

of newer novel agents, such as carlzomib/lenalidomide/

dexamethasone, daratumumab/lenalidomide/dexamethasone,

or elotuzumab/lenalidomide/dexamethasone, in relapsed

refractory multiple myeloma.

2-4

However, in ailand,

economic limitations have led to these new novel agents

being generally unavailable for this group of patients.

Although, lenalidomide plus dexamethasone has been

a standard treatment in Western countries in the past

decade, for developing countries, like ailand, this

combination only now represents a new hope for myeloma

patients.

In phase III clinical trials (MM-009

, MM-010

, the use

of lenalidomide plus dexamethasone in relapsed/refractory

multiple myeloma patients produced improvements

in overall survival and event-free survival compared

with high-dose dexamethasone alone.

5,6

However, in

these and other studies, lenalidomide was shown to be

associated with a higher rate of grade 3-4 hematologic

toxicity and a high incidence of thromboembolic events

compared with dexamethasone alone.

5-7

In a randomized,

controlled trial of patients with newly diagnosed multiple

myeloma, the combination of lenalidomide with either

high- or low-dose dexamethasone as an initial therapy

resulted in high rates of treatment response and event-free

survival.

Lenalidomide with low-dose dexamethasone

was associated with signicantly higher rates of overall

survival at 1 year, and lower rates of thromboembolic

events than lenalidomide with high-dose dexamethasone.

6-8

ere are few published data on the ecacy and

safety of lenalidomide in the treatment of refractory/

relapsed multiple myeloma patients in Asia. is study

is the rst to prospectively evaluate the administration

of lenalidomide for multiple myeloma in ailand. e

aim of the study was to investigate the ecacy and safety

of lenalidomide plus low-dose dexamethasone in ai

patients with refractory/relapsed multiple myeloma.

MATERIALS AND METHODS

Patients

Patients were eligible for inclusion in the study if

aged ≥18 years old and if they presented with progressive

multiple myeloma aer at least one previous treatment

regimen (e.g., vincristine, adriamycin, dexamethasone

[VAD]; liposomal doxorubicin, vincristine, dexamethasone;

high-dose dexamethasone; cyclophosphamide plus

dexamethasone; cyclophosphamide plus prednisolone;

bortezomib plus dexamethasone [VD]; thalidomide

plus dexamethasone; thalidomide, cyclophosphamide,

dexamethasone; bortezomib, thalidomide, dexamethasone;

VD plus panobinostat; dexamethasone, cyclophosphamide,

etoposide, cisplatin [DCEP]; or melphalan plus

prednisolone).

9,10

Patients were required to have adequate

hematologic and organ function, as demonstrated by

an absolute neutrophil count ≥1,500/µL, platelet count

≥75,000/µL, hemoglobin ≥7.5 g/dL, serum creatinine

<2.0 mg/dL, aspartate aminotransferase (AST), and

alanine aminotransferase (ALT) levels <3x the upper

limit of normal, all obtained 21 days prior to enrolment.

Additionally, patients were eligible for the study if they

had an Eastern Cooperative Oncology Group (ECOG)

performance status ≤2. Women with childbearing potential

were eligible if they agreed to use contraception and had

a negative pregnancy test before enrolment and took

monthly pregnancy tests thereaer. Exclusion criteria for

this study were dexamethasone intolerance or an allergy

to any of the study mediations; inadequate liver or renal

function at screening; ≥grade 2 peripheral neuropathy

within 14 days prior to screening; the diagnosis or treatment

of another malignancy within 2 years prior to screening

(with the exception of patients with non-melanoma skin

carcinoma who had undergone complete resection);

ongoing or active hepatitis B virus , hepatitis C virus or

HIV infection; uncontrolled comorbid cardiovascular

conditions within 6 months prior to screening; an

inability to take oral medication, or unwillingness to

comply with the drug administration requirements, or

have undergone a gastrointestinal procedure that could

interfere with oral absorption or tolerance of treatment;

and pregnancy. is study was approved by the Ethics

Review Committee of the Faculty of Medicine Siriraj

Hospital, Mahidol University (Si 650/2010).

Study design

is was a phase II, single-center, single-arm, open-

label study. Patients received oral lenalidomide 25 mg/

day on days 1–21 of a 28-day cycle and dexamethasone

40 mg once weekly. e lenalidomide dose was adjusted

according to patients’ creatinine clearance level, absolute

neutrophil count, and platelet count as recommended

by the European Myeloma Network.

Treatment was

continued until disease progression, as dened below.

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Kunacheewa et al.

romboembolic prophylaxis with aspirin 81 mg daily

was administered to patients with at least one risk factor

for thrombosis according to the International Myeloma

Working Group (IMWG) guidelines for the prevention

of thalidomide- and lenalidomide-associated thrombosis

in myeloma.

Complete blood count, blood chemistry and physical

examination were conducted every 15 days in the rst

treatment cycle and every 4 weeks thereaer.

Response criteria

Patient disease response and progression were

assessed according to the IMWG guidelines

and the

European Group for Blood and Marrow Transplant

criteria for multiple myeloma. A partial response was

dened as a reduction of M protein by at least 50% in

the serum and 90% in urine, or both.

9,10

A complete

response was dened as the complete disappearance of

M protein in serum and urine by immunoxation and

<5% plasma cell presence in the marrow. A very good

partial response (VGPR) was dened as a >90% reduction

of M protein in the serum and urine.

9,10

In patients with

light chain MM, the IMWG 2011 response criteria was

used. A >90% reduction of dierence in involved and

uninvolved serum FLC was classied as VGPR and the

CR criteria require a normal serum FLC ratio in addition

to CR criteria dened above.

Progressive disease was dened as a ≥25% increase

in serum M protein from best response, or an absolute

increase in serum M protein of >500 mg/dL compared to

the nadir value, or the appearance of a new bone lesion

or plasmacytoma that was increasing in size.

9,10

All toxicities were graded and attributed according

to the National Cancer Institute Common Toxicity

Criteria for Adverse Events, version 3.

Statistical analysis

e primary endpoint was the overall response

rate (ORR) at the end of the fourth treatment cycle.

Secondary endpoints included response to therapy

across all cycles (limited to eight cycles), toxicity, dose

adjustment due to toxicity, and time to progression

(TTP). Descriptive continuous data were summarized

using mean (SD), median (range) according to their

distribution and categories data were demonstrated as

percentage. Response to therapy was evaluated using the

chi-square test to compare treatment response between

patients who did or did not receive novel agents prior

to enrolment. The Mann–Whitney test was used to

compare the appropriate lenalidomide dose (the mean

eective dose following adjustment for adverse events)

in patients aged <60 and ≥60 years old. All patients were

included for analysis ORR and toxicities.

RESULTS

Patient characteristics

In total, 15 patients were enrolled in this study

between January 2011 and March 2012 at Siriraj Hospital,

Bangkok. e median age was 61 years old (range 23-74

years old). Among these patients, 11 had received a novel

agent in a prior treatment regimen, with a median of

two prior treatment regimens (range 1-7). Other baseline

characteristics and laboratory ndings are summarized

in Tables 1 and 2, respectively.

Treatment administration

Patients received a median of 10.25 treatment cycles

(range 1.8-15); nine received eight complete cycles and

were eligible for evaluation in this study. Two patients

progressed before the fourth treatment cycle (1 of 2

them previously underwent transplantation) and were

excluded from the study to receive another salvage therapy;

two patients progressed at the h and seventh cycles,

respectively, aer achieving a partial response at the fourth

cycle; one of these patients died as a result of infection

without neutropenia aer achieving a very good partial

response at the fourth cycle. Two patients underwent

autologous stem cell transplantation aer achieving a

complete response. Fig 1 illustrates the treatment pathway

of the enrolled patients.

The lenalidomide dose was adjusted according

to toxicity. In total, 105 doses of lenalidomide were

administered. Nine of the 15 patients received a reduced

lenalidomide dose, as shown in Table 2. e median

lenalidomide dose was 25 mg for patients aged ≤60 years

old and 15 mg for patients >60 years old (p = 0.101)

(Table 3).

Aspirin 81 mg/day was administered as

thromboprophylaxis for two patients (one patient with

diabetes mellitus, and one patient who was immobilized

due to plasmacytoma-related spinal cord compression)

for the duration of lenalidomide therapy, when their

platelet count was >50,000 μL. Another patient who

developed bilateral edema in the legs aer one cycle of

lenalidomide treatment also started aspirin 81 mg/day,

but this was stopped when no deep vein thrombosis was

detected by compression ultrasonography. However, aer

complete 8 cycles of the treatment, all patients who had

continued the treatment received aspirin 81 mg/day.

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TABLE 1. Patient demographics and clinical characteristics at baseline.

Characteristic All patients (n = 15)

N (%)

Age (years); Median (min–max) 61 (23–74)

Gender: Male 5 (33)

ISS staging

I 1 (20)

III 4 (80)

M protein isotype

Immunoglobulin G 7 (47)

Immunoglobulin A 2 (13)

Light chain 6 (40)

Plasmacytoma

Present 2 (13)

Number of previous treatment regimens

Median (min–max) 2 (1–7)

Prior regimen

Bortezomib 10 (67)

Thalidomide 7 (47)

Novel agent (bortezomib and/or thalidomide) 11 (73)

Stem cell transplantation 1 (7)

Laboratory

Hemoglobin, g/dL; Median (min–max) 10.1 (7.5–11.9)

Creatinine, mg/dL; Median (min–max) 0.9 (0.5–1.8)

LDH, U/L; Median (min–max) 383 (227–864)

 β-2-microglobulin,mg/L;Median(min–max) 4.75(2.28–19.3)

Abbreviations: ISS, international staging system; LDH, lactate dehydrogenase.

TABLE 2. Lenalidomide-dose adjustment during the study.

Reasons for dose adjustment n (%)

No. cycles administered 105

No.dose-adjustedcycles 14(13.3)

No. patients with dose reduction (%) 9 (60)

Reason for dose reduction, n (%)

Constitutional symptoms 4 (44.4)

Neutropenia 3 (33.3)

Renalinsufciency 3(33.3)

Infection 2 (22.2)

Anemia 1 (1.1)

Thrombocytopenia 1 (1.1)

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Kunacheewa et al.

TABLE 3. Lenalidomide-dose adjustment according to patient age.

Lenalidomide dose (mg/day)

≤60 years old >60 years old p value

Median (min–max) 25 (15–25) 15 (7.5–25) 0.101

Response to treatment

e median follow-up to treatment was 41 weeks

(range 7-60 weeks). e ORR was 86% and 73.3% at the

fourth treatment cycle and from all cycles, respectively.

Seven patients (46.7%) achieved at least a very good

partial response (VGPR) to treatment (Table 4). e

ORR of patients with prior regimen ≤2 was trend to be

better than those who received >2 prior line of therapy,

62% versus 39%, p=0.065. e ORR in patients who had

received prior bortezomib or thalidomide compared

with those who had not received prior novel therapy was

81.82% versus 100% (p = 0.15) and 63.6% versus 100%

(p = 0.13) at the fourth and from all cycles, respectively

(Table 5). e median time to response in patients who

achieved a response was 0.93 months (range 0.93–2.8).

To date, ve patients continue to receive lenalidomide

with low-dose dexamethasone. Of the remaining patients,

two underwent autologous stem cell transplantation, one

patient died from septic pneumonia without neutropenia,

two patients were refractory to this regimen, and ve

patients were considered to have progressive disease.

e median time to progression (TTP) for these seven

treatment-refractory patients was 8.9 months (range

1.8-14 months).

Fig 1. Treatment pathway and progression of patients during the study

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TABLE 4. Treatment response aer four treatment cycles, and aer all cycles.

All patients Prior bortezomib and/or Prior bortezomib Prior thalidomide

(n = 15) thalidomide (n = 11) (n = 10) (n = 7)

Response Fourth All Fourth All Fourth All Fourth All

treatment cycles treatment cycles treatment cycles treatment cycles

cycle cycle cycle cycle

ORR, n (%) 13 (86.7) 11 (73.3) 9 (81.8) 7 (63.6) 8 (77.8) 6 (60.0) 5 (71.4) 4 (57.1)

CR, n (%) 1 (6.7) 4 (26.7) 0 1 (9.1) 0 1 (10) 0 0

VGPR, n (%) 7 (46.7) 6 (40.0) 4 (36.4) 5 (45.5) 3 (30) 4 (40) 2 (28.6) 3 (42.9)

PR, n (%) 5 (33.3) 1 (6.7) 5 (45.5) 1 (9.1) 5 (50) 1 (10) 3 (42.9) 1 (14.3)

PD, n (%) 2 (13.3) 4 (26.7) 2 (18) 4 (36.4) 2 (20) 4 (40) 2 (28.6) 3 (42.9)

Treatment group

Overall response rate per treatment group, n (%)

Fourth cycle (n = 15) p value All cycles* (n = 13) p value

No prior bortezomib or thalidomide therapy 4 (100) 0.15 4 (100) 0.13

Prior bortezomib or thalidomide therapy 9 (81.8) 7 (63.6)

No prior bortezomib only 5 (100) 0.08 5 (100) 0.15

Prior bortezomib only 8 (80) 6 (60)

No prior thalidomide only 8 (100) 7 (87.5) 0.12

Prior thalidomide only 5 (71.43) 4 (57.1)

No prior SCT 13 (92.9) 0.2 11 (78.6) 0.6

Prior SCT 0 0

Abbreviations: CR, complete response; ORR, Overall response rate; PR, partial response; PD, progressive disease; VGPR, very good partial

response

TABLE 5. Comparison of treatment responses between patients who received novel agents and those who received

conventional therapy prior to lenalidomide administration.

* Median number of treatment cycles = 10.25. SCT, stem cell transplantation

Stem cell harvest and transplantation

The two patients who underwent stem cell

transplantation received lenalidomide plus low-dose

dexamethasone for seven and 10 cycles, respectively. Both

patients could successfully collect stem cell with high-

dose cyclophosphamide and 10 microgram/kilogram of

G-CSF. e rst patient, a 64-year-old male, achieved a

complete response at the sixth cycle and stem cells were

harvested successfully aer one procedure; his total

CD34+ cell count was 4.3 × 10

cells/kg following 2 days

of stem cell collection. e patient received melphalan

200 mg/m

as a conditioning regimen for 1 day, and

their response was re-evaluated 3 months aer stem cell

transplantation. is patient achieved a complete response

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1 month aer the transplantation. e second patient,

a 36-year-old female, received two stem cell harvesting

procedures because her initial overall CD34+ cell count

was 1.5 × 10

cells/kg following 3 consecutive days of

stem cell collection. She then received melphalan 200

mg/m

as a conditioning regimen and was admitted for

autologous stem cell transplantation. is patient also

achieved a complete response, 3 months aer stem cell

transplantation.

Treatment toxicity

e most common treatment-related toxicities

were hematologic events. Overall, 50% of patients had

at least one episode of hematologic toxicity, anemia,

and/or neutropenia. However, none of the patients

reported grade 3 or 4 neutropenia. e most common

non-hematologic toxicity was fatigue. ere was no

thrombosis events. Other adverse events in patients

aged <60 and ≥60 years old are shown in Fig 2. e

distribution of adverse events was similar in both age

groups, with notable dierences shown in the frequency

of grade 1-2 anemia, elevated ALT, and constipation

between the two groups (2.7%, 6.3%, and 1.8% versus

26.1%, 0.9%, and 9.9%, respectively; Fig 2). e overall

frequency and grade of toxicities across the 105 cycles

of treatment administered are shown in Fig 3.

One patient who achieved a stringent complete

response aer eight cycles reported progressive disease with

meningeal involvement following the twelh treatment

cycle.

DISCUSSION

Lenalidomide plus dexamethasone has demonstrated

clinical ecacy in both relapsed/refractory multiple

myeloma and newly diagnosed myeloma.

5-8

is is the rst

study to evaluate the use of lenalidomide plus low-dose

dexamethasone in relapsed/refractory multiple myeloma

patients in ailand. e ORR reported here (86.7%) is

consistent with those reported in prior multinational

phase II and phase III trials (MM-009, MM-010) using

this regimen.

5,6

Despite failing prior therapy with novel

agents such as bortezomib and/or thalidomide, these

patients demonstrated a positive response to lenalidomide

plus low-dose dexamethasone.

Fig 2. Frequency and grade of adverse events/toxicities by age group.

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There are few studies in the English literature

investigating the ecacy of novel regimens in treatment-

refractory multiple myeloma in Asia, with even fewer

studies investigating lenalidomide in these patients. At

our hospital in ailand, patients with newly diagnosed

multiple myeloma typically receive immunomodulatory

(IMiD)- or bortezomib-based regimens, or a combination

of both; if patients achieve a complete response, they then

receive approval for stem cell transplantation. For patients

with relapsed/refractory disease, the initial treatment

regimen may be switched; if patients are candidates for

transplantation, melphalan-based combinations are

not used. e majority of patients receive bortezomib

or IMiDs with cyclophosphamide-based conventional

chemotherapy, such as VAD or DCEP. e introduction

of lenalidomide further increases the treatment choice

for multiple myeloma, warranting its evaluation for

safety and ecacy in ai patients.

Bortezomib- and thalidomide-based salvage therapies

have demonstrated ecacy in Korean patients, with

ORR of 88% - 90% reported in one clinical study.

Similarly high response rates (100%) were observed in

an open-label study of Japanese patients with relapsed/

refractory multiple myeloma receiving a combination

of lenalidomide plus dexamethasone.

A retrospective

study investigating the use of thalidomide plus high-dose

dexamethasone in ailand in newly diagnosed and

treatment-refractory multiple myeloma patients reported

an ORR of 92%, which is similar only to that reported

in our study of treatment-refractory multiple myeloma

patients.

e high response rates reported here support

the available data in the literature and conrm the ecacy

of lenalidomide in treating refractory multiple myeloma

in an Asian population. However, heavily pretreated

patients showed lower response when compared with

patients who received ≤2 lines. In addition, the only

patient who exposed to transplantation did not response

well with this regimen.

Hematologic toxicities were the most common

treatment-related adverse events reported in this study.

However, in contrast to those reported in other studies,

the most frequently reported toxicity was anemia rather

than neutropenia.

5-8,16, 17

Both anemia and neutropenia

were manageable using transfusion and dose-reduction

strategies.

e median dose of lenalidomide in patients aged >60

years old was 15 mg/day. Patients received dose reductions

from the initial 25 mg/day primarily because of fatigue,

anemia, and neutropenia. Following lenalidomide-dose

adjustment, the toxicity prole improved in patients

Fig 3. Frequency and grade of adverse events/toxicities across all treatment cycles.

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aged ≥60 years old, although most of these patients

reported disease progression aer responding to therapy

at the fourth treatment cycle. Renal impairment was

another important factor leading to dose reduction. One

such patient developed grade 2 neutropenia, which was

successfully managed with dose reduction and appropriate

correction for the renal impairment.

Our study is limited by its open-label, single-arm

design, and the small size of the patient population.

While the focus of our study was on treatment response,

analyses incorporating progression-free and overall

survival may have provided further insights into the

ecacy of lenalidomide in treatment-experienced patients.

Despite these limitations, the ndings support the use of

lenalidomide in treatment-refractory multiple myeloma,

particularly in an Asian population. Our ndings are

consistent with data from multinational studies and also

those of other Asian studies.

5,6,14-16

A larger scale, long-

term randomized clinical trial would further conrm the

safety and ecacy of lenalidomide for multiple myeloma

in ai patients.

Novel agents can signicantly improve progression-

free survival and overall survival in multiple myeloma

patients. However, health insurance in ailand does

not cover the use of lenalidomide, except government

health coverage. Our study showed excellent outcomes

in this group of patients. In addition, this regimen is an

outpatient-based regimen. erefore, a socioeconomic

study is important for the further adaptation of this

regimen into all health coverage for patients’ benet.

In conclusion, the regimen of lenalidomide and

low-dose dexamethasone was found to be highly eective

in ai patients with relapsed and/or refractory multiple

myeloma; adverse events were manageable with an

acceptable toxicity prole. Our ndings suggest that

lenalidomide 15 mg/day is a safe and eective dose for

ai patients older than 60 years old. is combination

could be a new standard treatment in relapsed/refractory

multiple myeloma in ailand.

ACKNOWLEDGMENTS

We are grateful to all participating patients and our

clinical and laboratory colleagues for their collaboration

and support throughout this trial. e study was supported

by the ai Society of Hematology and the Faculty of

Medicine of Siriraj Hospital, Bangkok. Lenalidomide for

use in this study was donated by Celgene Corporation.

Medical editorial assistance was provided by Timothy

Stentiford of MediTech Media Asia. Medical editorial

assistance was supported by Celgene Corporation.

Conicts of interest: ere are no conicts of interest

to declare.

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