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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.
Efcacy 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 ecacy in the treatment of multiple myeloma.
In large global clinical studies, lenalidomide plus dexamethasone has demonstrated signicant 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 ecacy 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 eective in ai patients with relapsed and/
or refractory multiple myeloma, with a manageable adverse event prole. ese ndings suggest that lenalidomide
15 mg/day is a safe and eective 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.
1
Patients with relapsed and
treatment-refractory multiple myeloma require eective
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,
carlzomib, 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 carlzomib/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
5
, MM-010
6
, 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.
8
Lenalidomide with low-dose dexamethasone
was associated with signicantly 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 ecacy 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 ecacy 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 aer 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 thereaer. 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.
11
Treatment was
continued until disease progression, as dened 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.
12
Complete blood count, blood chemistry and physical
examination were conducted every 15 days in the rst
treatment cycle and every 4 weeks thereaer.
Response criteria
Patient disease response and progression were
assessed according to the IMWG guidelines
10
and the
European Group for Blood and Marrow Transplant
9
criteria for multiple myeloma. A partial response was
dened 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 dened as the complete disappearance of
M protein in serum and urine by immunoxation and
<5% plasma cell presence in the marrow. A very good
partial response (VGPR) was dened 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 dierence in involved and
uninvolved serum FLC was classied as VGPR and the
CR criteria require a normal serum FLC ratio in addition
to CR criteria dened above.
13
Progressive disease was dened 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
eective 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, aer achieving a partial response at the fourth
cycle; one of these patients died as a result of infection
without neutropenia aer achieving a very good partial
response at the fourth cycle. Two patients underwent
autologous stem cell transplantation aer 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 aer 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, aer
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-adjustedcycles 14(13.3)
No. patients with dose reduction (%) 9 (60)
Reason for dose reduction, n (%)
Constitutional symptoms 4 (44.4)
Neutropenia 3 (33.3)
Renalinsufciency 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 aer four treatment cycles, and aer 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 aer one procedure; his total
CD34+ cell count was 4.3 × 10
6
cells/kg following 2 days
of stem cell collection. e patient received melphalan
200 mg/m
2
as a conditioning regimen for 1 day, and
their response was re-evaluated 3 months aer stem cell
transplantation. is patient achieved a complete response
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1 month aer 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
6
cells/kg following 3 consecutive days of
stem cell collection. She then received melphalan 200
mg/m
2
as a conditioning regimen and was admitted for
autologous stem cell transplantation. is patient also
achieved a complete response, 3 months aer 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 dierences 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 aer eight cycles reported progressive disease with
meningeal involvement following the twelh treatment
cycle.
DISCUSSION
Lenalidomide plus dexamethasone has demonstrated
clinical ecacy 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 ecacy 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 ecacy in ai patients.
Bortezomib- and thalidomide-based salvage therapies
have demonstrated ecacy in Korean patients, with
ORR of 88% - 90% reported in one clinical study.
14
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.
15
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.
16
e high response rates reported here support
the available data in the literature and conrm the ecacy
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 prole improved in patients
Fig 3. Frequency and grade of adverse events/toxicities across all treatment cycles.
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Kunacheewa et al.
aged ≥60 years old, although most of these patients
reported disease progression aer 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
ecacy 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 conrm the
safety and ecacy of lenalidomide for multiple myeloma
in ai patients.
Novel agents can signicantly 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’ benet.
In conclusion, the regimen of lenalidomide and
low-dose dexamethasone was found to be highly eective
in ai patients with relapsed and/or refractory multiple
myeloma; adverse events were manageable with an
acceptable toxicity prole. Our ndings suggest that
lenalidomide 15 mg/day is a safe and eective 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.
Conicts of interest: ere are no conicts of interest
to declare.
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