Leukemia & Lymphoma

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Recent advances in the management of multiple

myeloma: clinical impact based on resource-
stratification. Consensus statement of the Asian
Myeloma Network at the 16th international
myeloma workshop

Daryl Tan, Jae Hoon Lee, Wenming Chen, Kazuyuki Shimizu, Jian Hou, Kenshi
Suzuki, Weerasak Nawarawong, Shang-Yi Huang, Chor Sang Chim, Kihyun
Kim, Lalit Kumar, Pankaj Malhotra, Wee Joo Chng, Brian Durie & for the
Asian Myeloma Network

To cite this article: Daryl Tan, Jae Hoon Lee, Wenming Chen, Kazuyuki Shimizu, Jian Hou,
Kenshi Suzuki, Weerasak Nawarawong, Shang-Yi Huang, Chor Sang Chim, Kihyun Kim, Lalit
Kumar, Pankaj Malhotra, Wee Joo Chng, Brian Durie & for the Asian Myeloma Network (2018):
Recent advances in the management of multiple myeloma: clinical impact based on resource-
stratification. Consensus statement of the Asian Myeloma Network at the 16th international
myeloma workshop, Leukemia & Lymphoma, DOI: 10.1080/10428194.2018.1427858

To link to this article: https://doi.org/10.1080/10428194.2018.1427858

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LEUKEMIA & LYMPHOMA, 2018
https://doi.org/10.1080/10428194.2018.1427858

REVIEW

Recent advances in the management of multiple myeloma: clinical impact

based on resource-stratification. Consensus statement of the Asian Myeloma
Network at the 16th international myeloma workshop
Daryl Tana,b, Jae Hoon Leec, Wenming Chend, Kazuyuki Shimizue, Jian Houf, Kenshi Suzukig,
Weerasak Nawarawongh, Shang-Yi Huangi, Chor Sang Chimj, Kihyun Kimk, Lalit Kumarl, Pankaj Malhotram,
Wee Joo Chngn,o and Brian Duriep; for the Asian Myeloma Network
a
Raffles Cancer Center, Raffles Hospital, Singapore; bDepartment of Hematology, Singapore General Hospital, Singapore; cGil Hospital,
Gachon University, Incheon, South Korea; dBeijing Chaoyang Hospital, Capital Medical University, Beijing, China; eHigashi Nagoya
National Hospital, National Hospital Organization, Nagoya, Japan; fDepartment of Haematology, Changzheng Hospital, The Second
Military Medical University, Shanghai, China; gDepartment of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan; hChiang
Mai Medical School, Maung, Thailand; iNational Taiwan University Hospital, Taipei, Taiwan; jQueen Mary Hospital, University of Hong
Kong, Hong Kong, China; kSamsung Medical Center, Sungkyunkwan University, Seoul, South Korea; lDepartment of Medical Oncology,
Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India; mDepartment of Internal Medicine,
Postgraduate Institute of Medical Education and Research, Chandigarh, India; nCancer Science Institute of Singapore, National
University of Singapore, Singapore; oDepartment of Haematology-Oncology, National University Cancer Institute of Singapore
National University Health System, Singapore; pCedars-Sinai Comprehensive Cancer Center, Los Angeles, CA, USA

ABSTRACT ARTICLE HISTORY

Predicated on our improved understanding of the disease biology, we have seen remarkable Received 20 September 2017
advances in the management of multiple myeloma over the past few years. Recently approved Revised 25 December 2017
drugs have radically transformed the treatment paradigm and improved survivals of myeloma Accepted 9 January 2018
patients. The progress has necessitated revision of the diagnostic criteria, risk-stratification and
KEYWORDS
response definition. The huge disparities in economy, healthcare infrastructure and access to Myeloma; resource-
novel drugs among different Asian countries will hinder the delivery of optimum myeloma care stratified; novel agents
to patients managed in resource-constrained environments. In the light of the tremendous
recent changes and evolution in myeloma management, it is timely that the resource-stratified
guidelines from the Asian Myeloma Network be revised to provide updated recommendations
for Asia physicians practicing under various healthcare reimbursement systems. This review will
highlight the most recent advances and our recommendations on how they could be integrated
in both resource-abundant and resource-constrained facilities.

Background and introduction
Multiple myeloma is the second most frequent hema-
tological malignancy, accounting for 1% of all new
cancer incidences and mortality globally [1]. The Asian
Myeloma Network (AMN) has reported rising incidence
of myeloma in Asia and that no major difference in
clinical or biological characteristics exists between
Asian and Western cases [2]. In view of the huge dis-
parity in healthcare across Asia, and with an aim to
provide a practical framework for planning resource-
appropriate myeloma care, the AMN formulated a set
of resource-stratified recommendations based on the
framework established by the Breast Health Global
Initiative where health-care resources were stratified
according to a four-tiered system on basis of available
resources (Table 1) [3,4]. Of late, the introduction of
novel drugs has resulted in remarkable progress in mye-
loma [5]. Since the publication of our guidelines, six
new drugs that are radically transforming the treatment
paradigm have been approved by the Food and Drug
Administration of America (FDA). Recent advances have
necessitated revision of disease definition, risk-stratifica-
tion and prognostication [6–8]. More stringent and pre-
cise criteria for response definition that include minimal
residual disease (MRD) measurement and treatment
algorithms that integrate high-dose therapy with
autologous stem cell transplantation (HDT-ASCT), tar-
geted therapies and immunotherapy have also evolved
[9]. Despite phenomenal breakthroughs, myeloma
remains incurable. Longer survivals would now translate
to higher cumulative prevalence, taxing prevailing
healthcare systems further. Clinical outcomes of
patients treated under resource-abundant and

CONTACT Daryl Tan tan_daryl@rafflesmedical.com Raffles Cancer Center, 585 North Bridge Road, #13-00 Raffles Hospital, 88770 Singapore,
Singapore
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
2 D. TAN ET AL.
Table 1. Four-tiered system based on available resources rele-
vant to program implementation [3].
Basic level Core resources or fundamental services that are abso-
lutely necessary for any cancer system to function;
basic-level services typically are applied in a single
clinical interaction
Limited level Second-tier resources or services that are intended to
produce major improvements in outcome such as
improved survival, and are attainable with limited
financial means and modest infrastructure; limited-
level services may involve single or multiple clinical
interactions
Enhanced level Third-tier resources or services that are optional in a
resource-constrained setting but are important and
should produce further improvements in outcome
and increase the number and quality of therapeutic
options and choices for patients
Maximal level High-level resources or services that may be used in
some high-resource countries and/or may be rec-
ommended by myeloma care guidelines that do
not adapt to resource constraints but that nonethe-
less should be considered a lower priority than
those resources or services listed in the basic, lim-
ited, or enhanced categories on the basis of
extreme cost and/or impracticality for broad use in
a resource-limited environment; to be useful, max-
imal-level resources typically depend on the exist-
ence and functionality of all lower level resources
resource-constrained facilities will continue to be more
disparate. In the light of rapid recent changes, the AMN
under the auspice of the International Myeloma
Foundation convened a meeting during the 16th
International Myeloma Workshop to discuss the clinical
impact of recent advances and provided consensus rec-
ommendations based on resource-stratification.
Resource-stratified consensus framework
As most countries in Asia are in the low- or middle-
income category, the latest International Myeloma
Working Group (IMWG) recommendations may not be
implementable. A resource-constrained center must
invest in facilities for myeloma care in a cost-effective,
stepwise fashion to achieve the best results with the
most rational allocation of resources. As myeloma is
rare, patients treated at higher-volume facilities report-
edly have a lower risk of mortality compared with
those treated at lower-volume facilities [10]. Basic
healthcare facilities will lack volume, expertise and
access to novel drugs. In order to avoid preventable
early mortalities, especially among patients with high-
risk disease, myeloma patients should not be managed
in settings with only basic facilities. Hence, our current
recommendations will be based on a three-tiered sys-
tem (limited/enhanced/maximum).
Diagnosis of multiple myeloma
In 2014, the IMWG revised the definition of myeloma
from being a disease defined primarily by symptoms
to one defined by biomarkers where serum free light
chains (SFLC) assay and accurate quantification of
bone marrow plasma cells (BMPC) now play vital roles
especially for patients with high-risk smoldering mye-
loma [6]. These changes are based on the observations
that having BMPC of
60%, involved to uninvolved
SFLC ratio of
100 or the presence of more than one
focal lesion with whole-body MRI was associated with
a 70–90% risk of progression to myeloma [11–13]. In
addition, early intervention in high-risk asymptomatic
patients has been shown to extend survival [14,15].
The preemptive approach of treating these patients
with ultra-high-risk smoldering myeloma could also
prevent the onset of organ damage which may further
escalate healthcare costs. To avoid missing the diagno-
sis of myeloma among asymptomatic patients, accur-
ate enumeration of BMPC is important. In clinical
practice, BMPC estimation is typically higher based on
trephine biopsy with CD138 immunohistochemical
staining compared to estimation on aspirate smear or
enumeration by flow cytometry [16]. As simple H&E
staining may frequently underestimate BMPC count,
immunohistochemical staining should not be omitted
for cost containment. Ambiguous cases could be
referred for opinion at more equipped facilities.
The definitions of the ‘CRAB’ criteria are recently
further fine-tuned. The IMWG recommends that meas-
ured or estimated glomerular filtration rates <40 mL/
min be used instead of a fixed serum creatinine con-
centration (>173 mmol/L or >2 mg/dL) as the latter
may be affected by weight, age and gender [6]. For
unclear cases where other concomitant comorbidities
may contribute to renal impairment, renal biopsy is
recommended [17]. Newer imaging techniques have
now shown greater sensitivity than radiographic bone
survey for defining myeloma bone disease (
1 sites of
osteolytic bone destruction
5 mm in size) [13,18]. The
revised IMWG criteria now recognize positron-emission
tomography-computed tomography (PET-CT) or low-
dose whole-body CT as valid methods to assess for
lytic bone lesions. It should be stressed that increased
uptake on PET-CT alone is not adequate for the diag-
nosis of myeloma and the CT portion of the PET-CT
scan is more important for assessment of osteolytic
bone destruction. Presence of osteoporosis or verte-
bral compression fractures alone in the absence of
lytic lesions is no longer accepted as evidence of bone
disease. Whole-body or axial MRI may be essential
especially if the skeletal survey or PET-CT doesn’t show
any bone lesion, or when an assessment for extraoss-
eous soft tissue masses is needed [13]. Physicians will
need to appreciate the limitations of the various

Table 2. Resource-adapted risk stratification.
Low risk
Limited ISS I without non-hyperdiploid karyo-
type and with normal LDH
Enhanced R-ISS I and age < 55
Maximum R-ISS I and age < 55 with standard-
risk signature on GEP or NGS
GEP: gene expression profiling; NGS: next generation sequencing; ISS: International Staging System; R-ISS: revised-ISS.
iFISH facility may not be available.
GEP or NGS complements, but does not substitute the R-ISS in risk-stratification.
imaging modalities and know when to refer patients
for more complex imaging.
Risk stratification
Multiple myeloma is clinically heterogeneous with
median survivals ranging from 3 to more than 10
years. Risk-stratification is hence vital for prognostica-
tion, defining treatment strategies and comparison of
outcomes between therapeutic trials. As novel treat-
ments may alter prognosis, prognostication systems
will have to evolve with changes in treatment para-
digms. The AMN previously recommended whenever
possible, the use of an integrated model of
International Staging System (ISS) with interphase
fluorescent in situ hybridization (iFISH) [4,19–21]. This
was recently combined with serum lactate dehydro-
genase (LDH) in the Revised-ISS (R-ISS) [7,22]. An ele-
vated LDH level is indicative of more aggressive
disease with higher proliferation rate and/or the pres-
ence of extramedullary involvement [23]. With an
improved prognostic power that has been validated,
the R-ISS is currently the preferred prognostication
tool [7]. Several gene expression signatures which
have been associated with high-risk disease are now
available as commercial platforms [24–26]. Specific
combinations of high-risk signatures with the ISS and
iFISH were demonstrated to further enhance prognos-
tic power [25,26]. Large scale sequencing studies have
become feasible with the advent of next generation
sequencing (NGS) and mutations detected by NGS
have been shown to further compliment current prog-
nostication methods [26]. Although highly precise,
genomic approaches may have limited usage in rou-
tine practice because of their complexity and costs.
In facilities with limited resources, the ISS and the
LDH level should be minimal risk-stratification parame-
ters since they are based on universally obtainable
laboratory measures (Table 2). Although the utilization
of conventional metaphase karyotyping has been
declining due to its lack of sensitivity compared to
iFISH, it remains the most easily performed cytogenetic
test with resource limitation. In the present era, it still
provides important prognostic information, especially
RESOURCE-STRATIFIED MANAGEMENT OF MYELOMA 3
Intermediate risk High risk
Neither low nor high risk ISS III plus non-hyperdiploid karyotype or
high LDH
R-ISS II R-ISS III
Neither low or high risk  R-ISS III
 High-risk signature with GEP or NGS
if a non-hyperdiploid karyotype is detected [19,27].
The critical iFISH panel done at centers with enhanced
facilities should include probes for 17p13 deletion,
t(4;14) and t(14;16) as they are part of the R-ISS.
However, an extended panel incorporating t(11;14),
t(14;20), gain(1q), del(1p) and del(13q) should be con-
sidered whenever possible, especially if the patient is
accrued in clinical trial as it is important to evaluate
for cytogenetic subgroups that may have preferential
sensitivity to certain novel agents [28,29]. A subopti-
mal response to induction and relapse within a year of
HDT-ASCT are also accurate predictors of dismal out-
comes [30,31].
Disease monitoring and response criteria
We previously recommended that response to treat-
ment be defined according to IMWG uniform response
criteria and evaluation of MRD be done only in context
of research [3,32]. While this recommendation remains
valid especially in resource-constrained facilities where
access to novel agents and HDT-ASCT is still not univer-
sal and a conventional CR remains a desirable treatment
goal that is attained by the minority, it may be inad-
equate in enhanced/maximal systems where response
assessment needs to evolve with the treatment advan-
ces. Novel drugs have tremendously improved the rates
and depth of response such that higher rates of CR are
now expected. New response grades that can further
discriminate responses that are deeper are needed.
Based on multiparameter flow cytometry (MFC) and
gene sequencing, the IMWG has defined new response
categories of MRD-negativity, with or without imaging-
based absence of extramedullary disease, to allow uni-
form reporting within and outside of clinical trials (Table
3) [9]. It is now apparent that benefits of CR come
mainly from the MRD-negative cases [33]. A recent
meta-analysis reported that newly diagnosed patients
who were MRD-negative after upfront therapy had sig-
nificantly better PFS and OS than counterparts who
were MRD-positive despite being in CR [34]. Currently,
MRD assessment is being implemented in most clinical
trials and many academic centers are applying it rou-
tinely. Although its role in informing treatment decisions
4 D. TAN ET AL.
Table 3. IMWG MRD criteria (requires a complete response).
Sustained MRD-negative MRD negativity in the marrow (NGF or
NGS, or both) and by imaging as
defined below, confirmed minimum of
one year apart. Subsequent evaluations
can be used to further specify the dur-
ation of negativity (e.g. MRD-negative
at five years)
Flow MRD-negative Absence of phenotypically aberrant clonal
plasma cells by NGF‡ on bone marrow
aspirates using the EuroFlow standard
operation procedure for MRD detection
in multiple myeloma (or validated
equivalent method) with a minimum
sensitivity of 1 in 105 nucleated cells
or higher
Sequencing DNA sequencing of bone marrow aspi-
MRD-negative rates using the LymphoSIGHT platform
(or validated equivalent method) with
a minimum sensitivity of 1 in 105
nucleated cells or higher
Imaging plus MRD negativity as defined by NGF or NGS
MRD-negative plus disappearance of every area of
increased tracer uptake found at base-
line or a preceding PET/CT or decrease
to less than mediastinal blood pool
SUV or decrease to less than that of
surrounding normal tissue
MRD: minimal residual disease; NGF: next generation flow; NGS: next gen-
eration sequencing.
is yet to be defined, it may be vital for assessment of
treatment efficacy and prognostication [33].
Additionally, MRD may eventually be used as a regula-
tory endpoint for drug approvals [35].
The two main methods for assessing MRD, MFC and
molecular sequencing, differ in various aspects, which
affect their clinical applicability. Next-generation multi-
color flow cytometry (NGF) which utilizes at least eight
markers has a sensitivity of 105 to 106 and up to
30% of patients found to be MRD-negative with con-
ventional MFC may become MRD-positive with NGF
[33,36]. Assessing MRD with molecular methods like
allele-specific oligonucleotide real-time quantitative
PCR (ASO RQ-PCR) has high sensitivity of up to 105,
but may be technically complex and is labor-intensive
[37]. More recently, NGS based on high-throughput
sequencing for clonally rearranged immunoglobulin
heavy chain and/or kappa light chain sequences may
find wider applicability [38,39]. With MFC, samples will
have to be processed within 24–48 h, but results may
be available immediately. With NGS however, samples
need not be processed immediately and hence
patients not treated in academic centers may still get
MRD assessment via commercial platforms. Monitoring
of MRD also includes an assessment of the extrame-
dullary compartment by PET-CT especially since extra-
medullary myeloma is now increasingly encountered
with extended survival of patients. A negative PET-CT
after HDT-ASCT is associated with superior survival
[40]. There are ongoing attempts to standardize
criteria for PET-CT reporting for myeloma with the
incorporation of semi-quantitative SUV evaluations
[41]. In the near future, newer imaging technologies
such as PET-MRI which is undergoing clinical evalua-
tions may provide more precise information without
radiation exposure [42,43].
Therapeutic monoclonal antibodies like daratumu-
mab may interfere with monoclonal protein assessment
and affect the accuracy of CR assignment [44]. Mass
spectrometry-based techniques are able to discriminate
the different proteins based on their masses and pre-
vent the inaccuracies, but are not available in most cen-
ters in Asia [45]. Anti-idiotype antibodies that neutralize
the offending drug (e.g. DARA IFE reflex assay) will be
commercially available and should be considered for
patients receiving monoclonal antibody therapy [46]. In
addition, MRD testing by MFC may also be affected
since CD38 is a critical surface marker exploited in MFC.
Specific CD38 antibody clones or reagents, together
with the most sensitive CD138-fluorochrome conju-
gates such as the current EuroFlow 2 tube eight-color
panel MFC platform may mitigate the problem and
allow treatment-independent assessment of MRD [9].
Front-line treatment: patients eligible for
transplantation
For newly diagnosed and physically fit patients
younger than 65–70 years, HDT-ASCT after induction
therapy remains standard [47]. The incorporation of
novel agents into induction regimens further improves
the survival outcomes [48,49]. Table 4 summarizes the
recommended front-line treatment options based on
resource availability. A three-drug combination that
includes a second generation IMiD like lenalidomide
and a proteasome inhibitor could be optimal, but if
reimbursement disallows, any bortezomib-based triplet
will be reasonable as the addition of a third agent like
thalidomide, cyclophosphamide or doxorubicin to bor-
tezomib-dexamethasone has consistently shown
higher response rates [50]. The Myeloma XI study has
recently demonstrated that for patients who failed to
achieve better than a PR with initial therapy of either
cyclophosphamide/lenalidomide/dexamethasone (CRD)
or cyclophosphamide/thalidomide/dexamethasone
(CTD), employing additional induction with bortezo-
mib/cyclophosphamide/dexamethasone (VCD) prior to
HDT-ASCT deepened response prior to and after HDT-
ASCT and improved PFS [51]. This approach could be
considered in centers where upfront use of novel
agents is not standard for all patients.
Recent studies comparing upfront HDT-ASCT versus
protracted course of novel agents with a deferred
Table 4. Resource-adapted recommendations by the AMN.
Resource level Limited Enhanced Maximal
Initial assessment  History and physical examination  Low-dose whole-body CT or
 Complete blood counts and differentials  PET-CT
 Peripheral blood smear for Rouleaux formation and circulating plasma cells  Whole-body MRI for ambiguous cases
 Chemistry screen including calcium, blood urea nitrogen, creatinine and albumin
 24 hour urine total protein and creatinine clearance
 Radiographic skeletal survey
 Electrocardiogram
 CT or MRI scan if indicated for assessment of extramedullary disease
 MUGA or echocardiography scan if anthracycline to be used
Tests to establish diagnosis  Serum and urine protein electrophoresis
 SFLC assay
 BMA and trephine biopsy
 Immunofixation
 Immunophenotyping by flow cytometry or immunohistochemistry
Staging and Risk stratification  ISS Interphase FISH  GEP
 LDH Minimum:  NGS
 Metaphase karyotyping -t(4;14) Complements
 Early Relapse/Progression (within 1 year of transplant) - t(14;16) R-ISS, but not mandatory
-17p13 del
Extended panel:
-t(11;14)
- t(14;20)
- gain(1q21)
- del(1p)
- del(13q
Response measurement and  Serum and urine protein electrophoresis  4- or 6-color MPF þ  NGF þ
disease monitoring  BMA and trephine biopsy  PET-CT þ  NGS þ
þ
 SFLC assay MRD assessment for deeper response  ASO RQ-PCR þ
þ
 MRI or CT scans for plasmacytoma or extramedullary disease evaluation and prognostication, not MRD assessment for deeper response
to inform treatment decisions evaluation and prognostication, not
to influence treatment decisions
Treatment for transplant-eligible  Cyclophosphamide/THAL/DEX  BTZ/LEN/DEX  Clinical trials
-Consider BTZ/Cyclophosphamide/DEX before HDT/ASCT if  PR  BTZ/Cyclophosphamide/DEX
 THAL/DEX  BTZ/Adriamycin/DEX
 DVd  BTZ/THAL/DEX
Mobilization:  BTZ/DEX
 G-CSF with or without prior cyclophosphamide chemotherapy  Rd
Mobilization:
 Plerixafor can be considered in
mobilization failures
Treatment for transplant-ineligible  MPT  Continuous Rd  Clinical trials
 THAL/DEX  BTZ/LEN/DEX
 Cyclophosphamide/THAL/Dex  VMP
 DVd  VMPT-VT
 BTZ/Dex
 BTZ/Cyclophosphamide/DEX
 BTZ/THAL/DEX
 BTZ/Adriamycin/DEX
RESOURCE-STRATIFIED MANAGEMENT OF MYELOMA

Treatment for relapsed/  THAL/DEX  CFZ/DEX  Clinical trials

refractory myeloma  DT-PACE  CFZ/LEN/DEX
(continued)
5
 6 D. TAN ET AL.

HDT-ASCT at first relapse have informed that the for-

MPT: melphalan/prednisolone/thalidomide; DVd: dexamethasone/vincristine/liposomal doxorubicin; DEX: dexamethasone; LEN: lenalidomide; BTZ: bortezomib; Pano: panobinostat; VMP: bortezomib/melphalan/pred-
nisolone; VMPT-VT: bortezomib/melphalan/prednisolone/thalidomide and bortezomib/thalidomide maintenance; VP-V: bortezomib/prednisolone and bortezomib maintenance; Rd: lenalidomide with lower-dose dexa-
mer approach results in superior CR, MRD-negativity
rates and PFS [52–54]. Although the frontline induction
regimen differed in the studies (lenalidomide/dexa-
Maximal

methasone [Rd], VCD and lenalidomide/bortezomib/

dexamethasone [VRD], respectively), they represent the
most commonly used novel induction combinations
currently. Despite the absence of an OS difference, it is
clear that novel agents are still not able to replace the
role of HDT-ASCT. Deferring HDT-ASCT would certainly
escalate healthcare costs and some patients may even-
tually become transplant-ineligible. Notwithstanding,
the IFM study has shown that regardless of HDT-ASCT,
POM/Cyclophosphamide/DEX

patients attaining MRD-negativity had similar superior

outcomes. As HDT-ASCT is still a very cost-effective
Enhanced

modality, whenever possible, patients treated in non-

transplant centers should always be referred for it.
DARA/LEN/DEX
DARA/BTZ/DEX
POM/CFZ/DEX
POM/BTZ/DEX

ELO/LEN/DEX
IXA/LEN/DEX

Currently, the role of tandem ASCT which was previ-

HDT/ASCT
POM/DEX

Pano/BTZ

ously found to be beneficial for patients who failed to

DARA

achieve at least a very good partial response (VGPR)

remains to be defined [55–58]. In a meta-analysis












based on phase III European studies, tandem trans-

plantation was shown to be beneficial for patients
with high-risk disease while the recently reported EMN
study suggests that tandem ASCT appears to be super-
ior in extending PFS compared with single ASCT after
Resources at the higher levels always depend on the existence and functionality of all lower-level resources.

induction therapy with limited cycles of VCD regimen

[56,57]. The phase III StaMINA study, however, indi-
cated that tandem ASCT followed by lenalidomide
maintenance gives similar outcomes as single ASCT
DEX/Cyclophosphamide/etoposide/cisplatin (DCEP)

followed by lenalidomide maintenance [58]. Most

methasone; CFZ: carfilzomib; POM: pomalidomide; DARA: daratumumab; ELO: elotuzumab.

patients in the study received VRD regimen as induc-

Limited

tion therapy for 2 to 12 months. Moreover, the tan-

dem-transplant cohort suffered from a large drop-out
rate, in part, reflecting actual patients’ reservation
against a second transplant. As such, tandem-ASCT
BTZ/Cyclophosphamide/DEX

should not be systemically applied as a routine.

Clarithromycin/LEN/DEX
Bendamustine/LEN/DEX
Bendamustine/BTZ/DEX

Nonetheless, for selected patients with high-risk dis-

BTZ/Adriamycin/DEX

ease or suboptimal response after the first ASCT, it

BTZ/THAL/DEX

Bendamustine
BTZ/LEN/DEX
BTZ/DT-PACE

may be an option especially in facilities where lenali-

BTZ/Doxil

domide and proteasome inhibitor cannot be given

together in induction or consolidation therapy.
RD

The StaMINA study also does not support the use














of consolidation after HDT/ASCT. Similarly, although

the role of consolidation remains to be defined, it
could be applied at the discretion of the treating phys-
ician after taking into consideration the cytogenetic
Table 4. Continued

risk, response attained after HDT-ASCT and resource

availability [58]. Based on major trials and meta-ana-
lysis, lenalidomide maintenance after a single ASCT
Resource level

clearly leads to better PFS and OS [59–61].

Lenalidomide lacks the neurotoxicity seen with pro-
longed use of thalidomide. However, the associated

increased risk of secondary cancers after HDT-ASCT
mandates a thorough discussion with patients before
its commencement. The costs of prolonged treatment
with lenalidomide can be prohibitive in most Asian
countries. Although maintenance with thalidomide
may be more financially feasible, precautions must be
taken against the development of significant neurotox-
icity which could preclude the use of bortezomib dur-
ing subsequent relapses [62]. Bortezomib maintenance
may considered for patients with t(4;14) [29]. Due to
the high treatment-related mortality and conflicting
reports from prospective studies allogeneic stem-cell
transplantation in frontline setting should be done
only in the context of clinical trials [63].
Risk-adapted approach
Individualizing therapy based on cytogenetic risk
remains a contentious issue and is largely dependent
on the healthcare reimbursement system. Although
optimal treatments for high-risk myeloma have yet to
be defined, prospective studies have informed that the
prognosis of high-risk patients may vary with the choice
of therapy [29]. In particular, the use of bortezomib-
based treatment for patients with t(4;14) has con-
sistently shown improved outcomes while the risk
associated with deletion 17p may be mitigated with
regimens that contain pomalidomide, carfilzomib and
daratumumab [48,64]. The hypothesis that high-risk
patients are most at risk for clonal evolution if they lack
durable response to initial therapies now prompts the
use of the most highly active combinations early to
reduce the emergence of resistance [65]. Patients with
high-risk disease in enhanced or maximal systems
should hence actively enroll in frontline trials that
incorporate various next-generation novel agents or
monoclonal antibodies where measurement of MRD is as
an endpoint. In resource-constrained facilities where
frontline access to novel agents may not be uniform, risk-
stratification may be a mean to triage resources and avail
novel agents to patients most at risk of early mortality [66].
Front-line treatment: patients ineligible for
transplantation
Transplant ineligible patients form a heterogeneous
group. Chronological age alone is not a reliable deter-
minant of functional reserve or the risk of complica-
tions from therapy. A comprehensive geriatric
assessment like the IMWG score should be applied
routinely before therapy to define the frailty profile of
the patient [67,68]. Based on age, comorbidities and
frailty, elderly patients can be divided into three
RESOURCE-STRATIFIED MANAGEMENT OF MYELOMA 7
treatment subgroups. Those who are ‘very fit’ or ‘fit’
may receive many of the regimens described for trans-
plant-eligible patients where three-drug combinations
are preferred while ‘unfit’ patients should receive a
two-drug regimen with an aim to achieve the max-
imum response with minimal treatment-related toxicity
[67,69]. The various bortezomib and lenalidomide com-
binations previously recommended will still remain
valid [4]. The recent SWOG S0777 study however, has
demonstrated that VRD improved PFS and OS with an
acceptable risk-benefit profile and could be the pre-
ferred three-drug combination if reimbursement per-
mits [70].
For patients with resource constraints, the combin-
ation of melphalan/prednisolone/thalidomide (MPT)
should be considered a minimal standard of care as it
has shown consistent improvements in PFS and even
OS [71]. The recently completed Frontline Investigation
Of Lenalidomide/Dexamethasone Versus Standard
Thalidomide (FIRST) trial showed that continuous Rd
given until disease progression was associated with a
significant improvement in PFS and OS compared to
fixed duration of Rd or MPT [72]. Adverse events and
subsequent hematologic malignancies were less fre-
quent with continuous Rd. Subgroup analysis of Asian
patients concluded that continuous Rd is safe and
effective [73]. A separate randomized study has
reported that alkylator-containing triplets of MPR and
CPR were not superior to the alkylator-free doublet Rd,
which was also associated with lower toxicities [74]. A
network meta-analysis demonstrated that Rd was asso-
ciated with significant PFS and OS advantage over
other first-line treatments including VMP, MPT and MP.
Although the optimal duration for induction therapy
after achievement of maximal response is still
unknown, data from the FIRST and other recent stud-
ies have consistently shown that continuous therapy
provide greater benefit including improved PFS2 (time
from random assignment until the second progression
or death) than fixed-duration therapy [72,75–77]. A
meta-analysis has raised concern that the risk of sec-
ondary primary malignancy may be higher in patients
receiving lenalidomide with melphalan [78]. Taken
together, the data represent a paradigm shift away
from alkylator-based regimens given for a fixed dur-
ation to an alkylator-free regimen given continuously.
Thus, in enhanced or maximal systems where upfront
access to bortezomib and lenalidomide may be univer-
sal, melphalan could be omitted whereas in facilities
with limited access to the two drugs, melphalan will
still remain an important backbone. Although using
thalidomide or bortezomib as continuous therapy may
8 D. TAN ET AL.
still appear efficacious, this has to be balanced against
the risk of neurotoxicity [75,76,79,80].
Management of relapse and refractory
multiple myeloma
Indications for starting treatment were recently
defined by the IMWG [81]. Synergistic combinations
that can overcome high-risk features and the continu-
ation of therapy till disease progression or the devel-
opment of intolerable toxicity in order to suppress
clonal evolution are now widely accepted as the sal-
vage strategies. This would inevitably compound treat-
ment costs and may not be feasible with resource
limitation. If reimbursement precludes continuous ther-
apy, the physician should strive to at least achieve a
plateau before stopping therapy. The ability of certain
new agents to mitigate adverse cytogenetic risks
would prompt the assessment for acquisition of new
mutations such as 17p deletion, 1q amplification or 1p
deletion [82]. Ability to manage the cumulative and
emergent toxicities from therapies is also important to
prevent premature discontinuation which will nega-
tively impact the eventual outcome [83]. Increased
options now allow for a more systematic approach to
relapsed/refractory disease.
First relapse
Patients with enhanced resources are more likely to be
receiving maintenance or continuous therapy at
relapse while those with limited resources are more
likely to relapse in the absence of therapy. For the lat-
ter group, the primary induction regimen may be
repeated if it accorded a durable remission of at least
six to nine months, whereas an alternative regimen
that incorporates at least one noncross resistant drug
should be considered if the remission duration with
the prior regimen is short. Bortezomib or lenalidomide
should be used if patients have never been exposed
to them. Patients with enhanced resources would have
been exposed to either or both of these two drugs
and hence a triplet with at least one new class of
agent or a change to a next-generation agent from
the same class should be considered [84,85]. Triplets,
whenever possible would be preferred to doublets as
they are associated with deeper remissions and better
survival outcomes. For patients treated under resource
constraints where novel triplets may not be feasible,
the addition of cyclophosphamide or clarithromycin is
a consideration. Albeit with limited data, they may
improve outcomes without substantially increasing
costs and toxicities [86,87]. Doublets such as Rd,
pomalidomide/dexamethasone (Pd), bortezomib/dexa-
methasone (Vd), or carfilzomib/dexamethasone (Kd)
are reasonable for frail patients who may not tolerate
triplet therapy. Salvage HDT-ASCT can be considered
for transplant-eligible patients who have yet to receive
one or had a durable post-HDT-ASCT remission of
more than 18 months. When high-risk genetics are
absent, this may be a more economical option in first
relapse compared to protracted courses of novel
agents [88].
Second and subsequent relapses
Management now has to be balanced against the
accumulation of toxicities from therapies. For patients
relapsing while receiving a doublet, it is prudent that
a triplet salvage be used to overcome genomic
instability [84,89,90]. Patients who have not been
exposed to monoclonal antibodies should consider
one of the combinations like daratumumab/bortezo-
mib/dexamethasone, daratumumab/lenalidomide/
dexamethasone or elotuzumab/lenalidomide/dexa-
methasone [91–93]. Combination of a bortezomib with
panobinostat may also be considered, but physicians
need to be aware of the peculiar toxicities of the com-
bination [94]. When rapid disease control is needed or
when patient develops plasma cell leukemia or extra-
medullary disease, intensive regimes like VDT-PACE
(bortezomib/dexamethasone/thalidomide/cisplatin/
doxorubicin/cyclophosphamide/etoposide) can be
considered [95]. As a result of clonal tides, it may be
reasonable to repeat the same agents previously used
[96]. Patients who have quadruple-refractory disease
(resistance to lenalidomide/pomalidomide/bortezo-
mib/carfilzomib) should receive salvage therapy that
incorporates a monoclonal antibody or enroll in a clin-
ical trial that explores other novel modalities. The vari-
ous resource-appropriate options in the salvage
setting based on rationally designed clinical trials are
listed in Table 4.
Drug access and clinical trials in Asia
It is clear from recent studies that novel agents are
able to induce deep remissions and even MRD-nega-
tivity, and gaining early access to them during relapse
is key to prolonging survivals. However, drug access
and healthcare reimbursement in many countries of
Asia are very limited [97]. For countries lacking
universal health coverage, only the affluent population
can afford novel drugs. Initiatives in the forms of
named-patient program or patient-assistance program
will be critical in availing drugs to patients [98] In

some countries, availability of generics or bio-similar
may help to defray costs of treatment, thereby allow-
ing more patients to be optimally treated [99].
Published experience with some of these drugs have
validated similar efficacy without increased toxicity
[100–102]. An important AMN initiative is the estab-
lishment of a clinical trial network across Asia with the
aims to avail novel drugs that may not yet be com-
mercially available in Asian countries, validate drug
responses and study peculiar patterns of adverse
events among Asian patients. Cross-border participa-
tion is encouraged as this allows patients from coun-
tries that lag behind in drug approvals or clinical
research to gain access to novel drugs. Physicians are
referred to the AMN website, https://www.myeloma.
org/research/asian-myeloma-network for the latest
updates on drug approvals and AMN clinical trials in Asia.
Supportive care
Supportive care plays an even more important role
now as patients are living longer with the burden of
disease complications as well as the cumulative side
effects of treatment. Although our previous consensus
for adjunctive management of venothromboembolism,
skeletal complications, infections and treatment-emer-
gent peripheral neuropathy would still remain valid,
emerging concerns pertaining to specific new drugs
will need to be addressed. In particular, as hepatitis B
virus (HBV) infection is highly endemic in Asia, a major
concern is the risk of its reactivation after the use of
anti-CD38 therapy. The experience with rituximab in
lymphoma treatment has informed that a high risk of
HBV reactivation may be encountered even among
patients who are HBsAg-negative, but anti-HBV core
antibody-positive [103,104]. This relates to a comprom-
ise of the B-cell associated humoral immunity when
CD20 is targeted. Although there has so far been no
reported case of HBV reactivation, in part due to the
lack of exposure of these drugs in Asia, the theoretical
risk of reactivation could be at least similar to that
seen with rituximab after plasma cells are targeted by
anti-CD38 therapy. In addition, the suppressive effect
of anti-CD38 antibodies on regulatory T-cells may
result in an exaggerated T-cell-mediated immuno-
logical response and hepatic attack upon recovery
from immunesuppression. Hence, it is mandatory to
screen for both HBsAg and anti-HBV core antibody for
all Asian patients who will be prescribed an anti-CD38
antibody. Pre-emptive prescription of prophylaxis and
monitoring of HBV load should be accessible at all lev-
els of resources. Resistance to lamivudine has been
reported especially in patients with high HBV titers
RESOURCE-STRATIFIED MANAGEMENT OF MYELOMA 9
and in patients given rituximab. As such, entacavir
might be the preferred anti-viral prophylaxis [105,106].
Conclusions
The management of myeloma is continuously evolv-
ing. Evidently, the key to improved survival outcomes
is the access to the latest quality diagnostics and novel
therapeutics. Healthcare resources have to be opti-
mized to achieve this goal. The role of clinicians and
researchers involved in global myeloma care should
be one of leveling the playing field such that one’s
birthplace does not determine one’s chance of surviv-
ing a treatable illness like myeloma. The AMN is com-
mitted to bridging the gap between patients treated
under resource-abundant and resource-constrained
facilities. We hope this resource-stratified framework,
used in conjunction with the available evidence, will
help to improve healthcare services in Asia to better
manage myeloma.
Search strategy and selection criteria
Articles for this review were found through searches of
PubMed, Medline, and references from relevant articles
by use of the search terms: ‘multiple myeloma,’ ’Asia,’
‘risk stratification,’ ’treatment’ and ‘cytogenetics.’ Trials
with the highest quality of study design were selected.
Only studies of adults, written in English, and pub-
lished between January 1985 and April 2017 were
included.
Acknowledgments
We thank Susie Novis, president of International Myeloma
Foundation (IMF), Dan Navid, vice president, global affairs of
IMF and Lisa Paik, senior vice president, clinical education
and research initiatives of IMF, Xuan Lam, medical affairs
assistant of IMF and Amirah Limayo, research project coord-
inator, IMF for their administrative efforts making this AMN
project possible.
Potential conflict of interest: Disclosure forms provided
by the authors are available with the full text of this article
online at https://doi.org/10.1080/10428194.2018.1427858.
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