Curr Hematol Malig Rep
DOI 10.1007/s11899-017-0370-5
MULTIPLE MYELOMA (P KAPOOR, SECTION EDITOR)
An Evidence-Based Approach to Myeloma Bone Disease
Nicholas Bingham 1 & Antonia Reale 2 & Andrew Spencer 1,2
# Springer Science+Business Media New York 2017
Abstract Multiple myeloma is an incurable clonal plasma
cell malignancy characterised by osteolytic bone lesions and
the presence of a monoclonal immunoglobulin. The bone dis-
ease caused by myeloma is a major cause of morbidity with
the related complications of pathological fractures,
hypercalcaemia and bone pain affecting both quality of life
and patient survival. The osteolytic lesions arise due to an
imbalance of osteoclast and osteoblast function, arising from
complex interactions between myeloma cells, bone marrow
stromal cells and the bone marrow microenvironment. These
advances in understanding of the pathophysiology have di-
rectly led to improvements in patient management and out-
comes. Recent advances in myeloma bone disease are
reviewed, including the role of novel and emerging therapies,
and evidence-based management strategies for myeloma bone
disease are discussed.
Keywords Multiple myeloma . Myeloma bone disease .
RANK/RANKL pathway
This article is part of the Topical Collection on Multiple Myeloma
Nicholas Bingham and Antonia Reale contributed equally to this work.
* Andrew Spencer
andrew.spencer@monash.edu
Nicholas Bingham
n.bingham@alfred.org.au
Antonia Reale
antonia.reale@monash.edu
1
Department of Haematology, Alfred Health, Melbourne, Victoria,
Australia
2
Australian Centre for Blood Disorders, Monash University,
Melbourne, Victoria, Australia
Introduction
Multiple myeloma MM is an incurable haematological malig-
nancy of clonal plasma cells, characterised by osteolytic bone
lesions and the presence of a monoclonal immunoglobulin [1].
MM accounts for 1% of all malignancies, with an incidence of
approximately 6 cases per 100,000 people, with a median age
at diagnosis of 65–70 years [2].
Osteolytic bone disease in MM develops due to increased
bone resorption by osteoclasts and reduced bone formation
through suppression of osteoblast function [3]. This imbal-
ance arises due to complex interactions between MM cells,
bone marrow stromal cells and osteoclasts [4]. The osteolytic
lesions predominantly affect the axial skeleton and proximal
long bones, although any bone can be affected [5]. Osteolytic
bone lesions lead to complications known as skeletal-related
events (SREs), which are defined as bone pain, pathological
f r a c t u r e s , n e ed fo r s u rg e r y or ra d i ot h e r a p y a n d
hypercalcaemia [6]. Spinal instability and spinal cord or nerve
root compression can also occur from bone disease [7].
Treatment of MM bone disease is required to reduce SREs
and maintain or improve quality of life and reduce treatment
cost [8].
Prevalence and Impact of Bone Disease
Bone disease affects 80–90% of patients with MM during
their disease course [3]. Bone disease can take the form of a
single osteolytic lesion (solitary plasmacytoma), diffuse
osteopenia or multiple lytic lesions. Osteopenia is found in
up to 90% of MM patients [9] while lytic lesions occur in at
least 80% [10]. Untreated patients with bone lesions typically
have >2 SREs per year [11]. Pathological fractures occur in
40% of patients in the first year after diagnosis and 60% of

patients during the disease course [12]. Spinal cord compres-
sion can affect up to 20% of patients [7]. Symptoms related to
bone disease and SREs are a major cause of reduced quality of
life, mobility and performance status in MM patients [13].
Bone pain is the first reported symptom in 70% of cases
[10]. Aside from reduced quality of life, pathological fractures
also have a negative impact on survival; compared to patients
without fractures, there is a 20% increase in mortality [3].
Moreover, the number of bone lesions has been shown to
correlate with prognosis [14]. Osteosclerotic lesions in MM
are rare, being found in less than 3% of cases [15], although
they are seen more frequently in the related plasma cell dys-
crasia POEMS syndrome [16].
Pathophysiology
MM plasma cells accumulate in the bone marrow where they
promote unbalanced bone remodelling through increased os-
teoclast activity and suppressed osteoblast activity [3]. Several
theories have been proposed to explain this uncoupling of the
bone remodelling process (see Fig. 1).
One key mechanism is the adherence of MM cells to bone
marrow stromal cells (BMSCs) that stimulate secretion of pro-
osteoclastogenic and anti-osteoblastogenic cytokines. Cell-to-
cell adhesion is mediated by integrins such as VLA-4
expressed by MM cells and VCAM-1 expressed on BMSCs
[17, 18]. Similarly, ANGPTL4, an extracellular matrix protein,
mediates interaction between MM cells and BMSCs during the
early stages of MM bone disease and has a role in the
uncoupling of angiogenesis and osteogenesis [19]. MM cells
produce cytokines such as IL-6, chemokine (C-C motif) ligand
3 (CCL3) and dickkopf-1 (DKK1) that directly or indirectly
affect bone cell activity [4]. Many of the osteoclastogenic cy-
tokines converge on the receptor activator of nuclear factor-κB
(RANK) pathway that is of central importance in osteoclast
differentiation and activation [20, 21]. RANK is a transmem-
brane signalling receptor located on the surface of osteoclast
precursors whereas RANK ligand (RANKL) is secreted by
activated lymphocytes and also expressed on BMSCs and os-
teoblasts. Through the NF-κB and JunN terminal kinase path-
ways, the RANK/RANKL signal enhances osteoclast survival
and increases bone resorption [20].
The RANK/RANKL pathway is perturbed in MM. MM
cells can disrupt the interplay between RANKL and its soluble
decoy receptor osteoprotegerin (OPG) with increased
RANKL expression and decreased OPG expression promot-
ing the formation and activation of osteoclasts [22].
Additionally, T cells derived from the peripheral blood mono-
nuclear cells (PBMCs) of MM patients with osteolysis have
been shown to support the development and survival of oste-
oclasts through expression of high levels of RANKL [23].
These T cells also produce IL-17, which plays a key role in
Curr Hematol Malig Rep
the progression of bone disease in MM by increasing RANKL
expression on BMSCs [24]. The Notch signalling pathway
also drives osteoclast activation through the RANK/RANKL
pathway. Activation of the Notch pathway in MM and
BMSCs leads to increased secretion of RANKL, and this in
turn leads to the upregulation of the receptor Notch2 on pre-
osteoclasts, stimulating osteoclast differentiation via an auto-
crine RANKL signalling pathway [25]. Finally, MM cells
may also secrete parathyroid hormone-related protein
(PTHrP) and Annexin II. PTHrP increases expression of
RANKL through stimulation of osteoblasts and bone marrow
stromal cells [26]. Annexin II stimulates osteoclast growth and
increases bone resorption by stimulating the expression of
RANK on BMSCs [3].
There are also a number of RANK/RANKL independent
mechanisms of osteoclast stimulation in MM. BMSCs express
growth differentiation factor 15 (GDF15), a member of the
transforming growth factor-beta family that both increases
osteoclast differentiation and inhibits osteoblast differentiation
in vitro. Serum GDF15 levels are elevated in patients with
advanced osteolytic bone disease compared to the levels in
patients with no lesions [27]. EphrinB2 is a member of the
Ephrin family and binds to its specific receptor, EphB4.
EphrinB2/EphB4 plays an important role in bone remodel-
ling; the bidirectional signal transduction allows transition
from bone resorption to bone formation. MM cells negatively
regulate EphrinB2/EphB4 expression, leading to uncoupling
of bone remodelling process [3]. PU.1 is a transcription factor
that controls early OCL differentiation from myeloid precur-
sors [28]. PU.1-deficient mice show marked inhibition of
OCL differentiation [29]. In contrast, extracellular signal-
regulated kinase (ERK) mediates the later stages of OCL dif-
ferentiation and continuing OCL survival [30];
phosphorylated-ERK is critical for MM cell growth [31].
Inhibition of these pathways induces apoptosis of OCL [30].
While some pathways stimulate osteoclast development in
MM, other pathways are altered leading to suppression of
osteoblast maturation and/or function. Runt-related transcrip-
tion factor 2 (Runx2) is suppressed in MM by tumour necrosis
factor-alpha (TNF-α) and Gfi1. TNF-alpha is an inflammatory
cytokine that is increased in MM [32, 33] whereas Gfi1 is a
transcriptional repressor of Runx2 and increased levels of
Gfi1 have been reported in MM patients [34]. IL-7 has been
implicated in the Runx2-mediated inhibition in osteoblast pro-
genitors and in the consequent suppression of osteoblast for-
mation [35].
The loss of osteoblast numbers and function as MM pro-
gresses has been recognised as a reflection of tumour evolu-
tion, with a loss of the MM cell dependence on osteoblast-
derived factors or the increased compensatory growth factors
that are released through bone resorption, e.g., IGF-I [36].
CCL3 is a pro-inflammatory cytokine involved in the recruit-
ment and differentiation of osteoclast precursors. It is
Curr Hematol Malig Rep
Fig. 1 The pathophysiology of bone disease in myeloma. The adherence
of MM cells to bone marrow stromal cells (BMSCs) stimulates the
secretion of pro-osteoclastogenic and anti-osteoblastogenic cytokines in
the bone marrow microenvironment. Cell-to-cell adhesion is mediated by
integrins such as VLA-4 expressed by MM cells and VCAM-1 expressed
on BMSCs. MM cells, stromal cells and T cells produce several pro-
osteoclastogenic factors (including RANKL, CCL3, IL-3, IL-6, IL-17,
PTHrP) that directly or indirectly promote OC differentiation from OC
precursors, hence OC resorptive activity. The expression of OPG, the
RANKL-soluble decoy receptor, by stromal cells is reduced, and
inactivation of OPG through binding to syndecan-1 on the surface of
MM cells is also observed, thus favouring the RANKL/OPG ratio
upregulated in MM bone marrow, promotes tumour progres-
sion and bone lysis [3] and impairs osteoblast function but has
no effect on osteoblast differentiation [37]. In early MM, there
is reduced osteoblast function despite preserved numbers,
likely driven by elevated CCL3 expression. Later in disease
evolution, osteoblast suppression is manifested by both re-
duced differentiation and impaired function [38].
Furthermore, CCL3 levels fall while DKK1 levels rise, sug-
gesting that disruption of Wnt signalling may play a role at
this stage [39]. Wnt is a ligand that binds to the low-density
lipoprotein receptor-related protein with subsequent stimula-
tion of osteoblastogenesis; sclerostin, like DKK1, is a Wnt
antagonist, also found at high levels in MM patients [40]. As
the disease progresses, MM cells lose their dependence on
BMSCs. Levels of several stromal-derived MM growth/
survival factors (such as BAFF [TNFSF13B], IL6, IL6R,
VEGFA) fall in advanced MM. This reflects a disturbance of
stromal physiology, when other factors become important [3,
4, 38]. The consistent downregulation of adhesion molecules
LFA-1 (ITGB2), VLA-4 (ITGA4) and VCAM1 in advanced
disease reflects reduced dependence of tumour cells on adhe-
sive interactions at this stage [38].
The typical uncoupling of osteoclast and osteoblast func-
tion occurs in advanced MM; however, changes in osteoblast
towards RANKL. On the other hand, OCs produce several growth
factors (e.g., IL-6) which promote the growth and survival of MM cells.
A number of other pathways are altered leading to suppression of OB
maturation and/or function. MM cells produce high levels of DKK1
which inhibits OB activity. Runx2 is suppressed by factors secreted by
MM cells such as TNF-α and IL-7. Furthermore, MM cells directly
induce OB apoptosis via TRAIL. RANKL receptor activator of nuclear
factor-κB ligand, CCL3 chemokine (C-C motif) ligand 3, IL-3/6/7/17
interleukin 3/6/7/17, OPG osteoprotegerin, OC osteoclast, pOC pre-
osteoclast, OB osteoblast, DKK1 dickkopf-1, TNF-α tumour necrosis
factor-alpha, Runx2 Runt-related transcription factor 2, TRAIL TNF-
related apoptosis-inducing ligand, MM Multiple myeloma
function have been noted prior to the development of overt
bone loss in MM [38, 41]. MM cells establish intimate rela-
tionships with bone cells and are likely to exert effects soon
after their arrival in the bone marrow. Abnormal bone metab-
olism has been described also in asymptomatic or smoulder-
ing MM (SMM) or MGUS, reinforcing the concept that bone
physiology is affected even while the tumour is in its pre-
malignant phase [42]. This provides a rationale for clinical
intervention at an early stage of disease when patients are still
asymptomatic, supporting the recent change in recommenda-
tions regarding treatment of high-risk SMM [43].
Imaging in Myelomatous Bone Disease
Diagnosis
Plain radiographs of the axial and appendicular skeleton (the
skeletal survey—SS) are the gold standard for the detection of
osteolytic lesions in MM [8]. Importantly, however, the SS has
several limitations: quantification of lesion size is not possible
and it has low sensitivity, requiring loss of at least 30% of
cortical bone to be detected [5]. Whole-body low-dose
computerised tomography (WBLD CT) has a higher

sensitivity than plain radiographs [5]. It detects more bone
lesions and more lesions at risk of fracture and upstaged al-
most 50% of patients in one study [44]. Moreover, lesions can
be quantified more accurately. Functional imaging, such as
18F-fluorodeoxyglucose positron emission tomography com-
bined with CT improves upon the sensitivity of CT (reportedly
between 80 and 90%) with a specificity of 80–100% [5]. PET/
CT identifies more lesions that SS alone [45] and results at
diagnosis correlate with survival [14]. PET/CT may be partic-
ularly useful in cases of solitary plasmacytoma as available
evidence suggests that it upgrades the diagnosis in approxi-
mately 42% of patients, significantly altering management in
these cases [46].
Magnetic resonance imaging MRI and Sestamibi scans,
unlike CT and SS, are used to detect focal infiltration of bone
marrow rather than lytic lesions. Sestamibi scans utilise
technetium-99-m labelled hexakis-2-methoxy-isobutyl-
isonitrite (99mTc-sestamibi) that accumulates in tissues with
high mitochondrial activation such as MM. The degree of
uptake has been shown to correlate with disease severity in
MM, but the scan is limited by failure to identify lytic lesions
at risk of fracture [5]. MRI is useful in MM and complements
SS and WBCT by detecting marrow infiltration in contrast to
lytic lesions. MRI is inferior to WBCT in detecting bony le-
sions but detects bone marrow infiltration in the absence of
lytic lesions. MRI is superior to SS and upgrades diagnosis in
68% of cases. Furthermore, in the evaluation of SMM, the
presence of more than one focal lesion on MRI is associated
with a 70% risk of progression to symptomatic MM in 2 years
[47] and MRI findings have also been shown to correlate with
survival and treatment response [14]. The presence of more
than one focal lesion on MRI of at least 5 mm in size is now
considered a myeloma-defining event [48].
Assessment of Disease Response
Current response criteria are based on laboratory parameters
as response to therapy cannot be determined with SS or
WBLDCT as osteolytic lesions rarely improve with therapy
[49]; additionally, SS do not enable the evaluation of
extramedullary disease. In contrast, improvement on com-
bined PET/CT imaging after treatment correlates with both
clinical improvement and prolonged survival [50, 51].
Alternatively, whole-body MRI can be used if available [52]
as can Sestamibi scans, as results after therapy correlate with
biochemical markers of disease activity [53].
Bone Turnover Markers in Myeloma
A better understanding of the pathophysiology of MM has led
to the discovery of a range of potential bone turnover markers,
many of which have also been investigated as therapeutic
Curr Hematol Malig Rep
targets. Bone turnover markers can reflect either bone resorp-
tion or bone formation, but the clinical utility of many of these
markers remains unclear. However, the identification of a val-
idated and reliable marker of disease activity could minimise
the requirement for invasive procedures, expensive imaging
and radiation exposure [54].
The most commonly used marker is C-terminal type 1 col-
lagen telopeptide (CTX-1, C-telopeptide). CTX-1 is a break-
down product of collagen and is used as a marker of bone
resorption [55]. Levels are high at diagnosis and highest in
patients with significant bone involvement; this can reflect
marrow infiltration rather than purely lytic lesions. CTX-1 is
renally excreted and is therefore difficult to interpret in severe
renal failure (eGFR <30). Patients who respond to treatment
have a reduction in CTX-1 at 3 months. Relapse is similarly
preceded by a rise in CTX-1 3–6 months prior to changes on
imaging, so CTX-1 has potential as a marker of early relapse.
Bisphosphonate therapy reduces the CTX-1 level, but there is
still a statistically significant change in CTX-1 level prior to
relapse, thus CTX-1 retains potential as a biomarker in pa-
tients on bisphosphonates [55].
Other markers reported in the literature include DKK-1 and
RANKL (used as markers of MM cell growth and develop-
ment of lytic lesions), TRACP-5b, (a marker of osteoclast
function) and osteocalcin and bone alkaline phosphatase
(markers of bone formation). However, the use of these
markers is generally limited to research settings.
Management of Myeloma Bone Disease
Systemic control of MM via the modulation of bone disease
pathophysiology is the cornerstone of treatment for MM bone
disease. More specific MM bone disease therapies, includes
bisphosphonates, radiotherapy, surgery and balloon
kyphoplasty, with newer investigational therapies remaining
an active area of current research.
Bisphosphonates
Bisphosphonates (BPs) are recommended for all patients with
MM requiring front-line therapy, regardless of the presence of
bone disease at diagnosis. Moreover, BPs are recommended
for those with low- and intermediate-risk SMM if osteoporosis
is identified by dual-energy x-ray absorptiometry scan, at
doses used in patients with osteoporosis. For high-risk
SMM, or if one cannot differentiate between MM-related ver-
sus age-related bone loss, the treating physician should con-
sider using the dosing and schedule of BPs as for symptomatic
MM, especially in patients with abnormal MRIs [8].
The BPs zoledronate (ZOL), pamidronate (PAM) and
clodronate (CLO) reduce SREs and control bone pain [8, 56].
There is no single bisphosphonate that shows benefit over
Curr Hematol Malig Rep
others with regard to reduction in SREs, bone pain or overall
survival, although ZOL improved overall survival by
10 months in MM patients with lytic lesions at diagnosis when
compared to clodronate [57]. ZOL use in newly diagnosed MM
patients also results in a reduced rate of SREs when compared
with CLO [8], whereas intravenous (IV) ZOL and PAM exhibit
comparable efficacy in reducing SREs [58]. While no data
demonstrate a survival advantage for PAM, both PAM 30 and
90 mg have shown comparable effects for preventing SREs and
PAM 30 mg is associated with a lower risk of both
osteonecrosis of the jaw (ONJ) and nephrotoxicity compared
to PAM 90 mg [8]. When feasible, IV administration of BPs is
preferred with infusion times ranging from 15 min for ZOL to 2
to 4 h for PAM. Oral administration remains an option for
patients who cannot receive regular hospital care or in-home
nursing visits. IV BPs should be administered at 3- to 4-week
intervals to all patients with active MM [6, 8]. While the rec-
ommended dosing schedule for ZOL is that it be given 4 week-
ly, a recent study has shown that the dosing of ZOL at 12-
weekly intervals is not associated with an increased risk of
SREs compared to 4 weekly [59]. While in all randomized,
placebo-controlled trials, the bisphosphonates were given for
a maximum period of 2 years, in the MRC-IX trial, the
bisphosphonates were given until disease progression [60].
The subset of patients who received ZOL for more than 2 years
continued to experience a reduction in SREs and an improve-
ment of overall survival compared with clodronate. However,
there was no sub-analysis according to the response status of
the patients, and thus it is not clear if the continuous use of ZOL
produces similar results in patients who have achieved a CR,
sCR, very good partial response (VGPR) or PR. Therefore,
ZOL should be administered until disease progression, except
in patients who have achieved CR or VGPR [8, 59] and had no
lytic disease at diagnosis. There are no data supporting the
continuous use of pamidronate, thus PAM should be adminis-
tered for 2 years and then at the physician’s discretion in pa-
tients with active disease. PAM therapy should be resumed
after disease relapse [8].
Potential adverse events (AEs) associated with BP admin-
istration include hypocalcaemia and hypophosphataemia, GI
events after oral administration, inflammatory reactions at the
injection site and acute-phase reactions after IVadministration
of amino BPs. Renal impairment and ONJ represent infre-
quent but potentially serious AEs.
Preventive strategies should be adopted to avoid ONJ.
Patients should receive a comprehensive dental examination
and education regarding optimal dental hygiene, and existing
dental conditions should be treated before initiating BP thera-
py. After BP treatment initiation, unnecessary invasive dental
procedures should be avoided and dental health status should
be monitored annually [61]. Patients should be monitored for
compromised renal function by measuring creatinine clear-
ance (CrCl) prior to each IV BP infusion. Patients with mild
to moderate renal impairment (CrCl rate of 30 to 60 mL/min)
should receive reduced doses of CLO and ZOL under close
clinical monitoring. No change to ZOL infusion time is rec-
ommended. PAM should be administered via extended infu-
sion duration (>4 h) and clinicians should consider initial dose
reduction in patients with renal impairment. PAM and ZOL
are not recommended for patients with CrCl <30 mL/min.
PAM has been rarely associated with nephrotic syndrome
due to focal sclerosing glomerulosclerosis [62] with most
cases appearing dose related and cessation of PAM was asso-
ciated with improvement in renal function [63].
Calcium and Vitamin D
Hypocalcaemia is a complication of bisphosphonate therapy.
This can be prevented by the administration of oral calcium
and vitamin D3. Patients should routinely receive calcium
(600 mg per day) and vitamin D3 (400 IU per day) supple-
mentation. Calcium supplementation should be used with cau-
tion in patients with renal insufficiency [6, 8].
Denosumab
Denosumab is a fully human monoclonal antibody specific to
RANKL that inhibits the formation, function and survival of
osteoclasts, thus decreasing cancer-mediated bone destruc-
tion. In a large randomized trial of patients with evidence of
bone disease including MM, denosumab was not inferior to
ZOL and reduced the risk of SREs compared with ZOL; how-
ever, overall survival at 1 year was less in MM patients receiv-
ing denosumab compared to patients receiving ZOL (83 vs
97%) [64, 65]. These results are difficult to interpret as the
study was not powered to ask a question about the two agents
specifically in MM with resulting small numbers of MM pa-
tients and imbalances in baseline disease characteristics con-
founding any post hoc evaluation. The toxicity of denosumab
is low, most commonly causing asthenia and hypocalcaemia,
with a rate of ONJ comparable to ZOL. Denosumab may lead
to increased infection rates through its anti-RANKL effect so
caution is needed in immunocomprised MM patients [64]. A
larger international study (NCT01345019) is underway and
will provide further evidence regarding the efficacy and safety
of denosumab in MM when compared to ZOL. Denosumab
can currently be given in MM patients only in the rare cases of
hypercalcaemia resistant to BPs [66].
Anti-MM Therapies—Proteasome Inhibitors
Several studies have confirmed the positive effects of PIs on
bone formation and resorption markers [67–70]; moreover, a
retrospective analysis of bortezomib-treated MM patients
demonstrated a correlation between the bone formation mark-
er alkaline phosphatase and disease response. A decrease in

DKK-1 serum levels and other markers of bone resorption
(such as TRAP-5b, CTX and soluble RANKL) has also been
observed after bortezomib treatment. No significant changes
in these markers were detected in non responders [54].
Histological studies have shown that MM patients who re-
spond to bortezomib have an increase in the number of oste-
oblastic cells/mm2 of bone tissue compared to non-responders
[69]. The positive anabolic effect of bortezomib on bone
healing and new matrix deposition was confirmed by bone
imaging techniques such as dual-energy X-ray absorptiometry
(DEXA), technetium-99 m-(99mTc-) methyl-diphosphonate
(MDP) bone scan and micro-CT measurements on biopsy
specimens [33].
In addition to its clinical anti-tumour effect, the second
generation PI carfilzomib (PR-171) has been shown to reverse
osteoblast inhibition and improve bone disease in an in vivo
MM mouse model [71]. Carfilzomib stimulates mesenchymal
stromal cell (MSC) differentiation into osteoblasts, and oste-
oblasts derived from MM patient MSCs when treated with
carfilzomib display increased bone formation in vitro [71,
72]. At doses toxic to MM cells, carfilzomib also inhibits
osteoclast differentiation and function without affecting the
precursor viability. This effect is due in part to disruption of
RANKL-induced NF-κB signalling [33]. A recent retrospec-
tive analysis of 67 relapsed or refractory MM patients treated
with carfilzomib demonstrated that elevation in ALP levels
correlated with response to the treatment [73]. Likewise, other
second-generation PIs such as ixazomib and oprozomib inhib-
it osteoclastogenesis and bone resorption and promote osteo-
blastogenesis and activity [33].
Anti-MM Therapies—Immunomodulatory Drugs
Thalidomide, and its second-generation derivatives
lenalidomide and pomalidomide, have direct anti-tumour
effects via several different mechanisms [74]. IMiDs have
been reported to prevent the adhesion of MM cells to non-
MM cells in the BM microenvironment including BMSCs,
osteoclasts and immune cells. This breaks the pathophysi-
ological cycle of MM by reducing MM-induced osteoclas-
togenesis and the resultant growth factors released during
bone destruction [74, 75].
Lenalidomide inhibits osteoclast formation and activation
by inhibiting key factors, such as PU.1 and pERK, during
osteoclastogenesis and also by reducing MM burden [29,
75]. Additionally, lenalidomide has been shown to decrease
RANKL secreted by BMSCs derived from MM and down-
regulate cathepsin K (which is secreted by osteoclasts and
induces matrix degradation during bone resorption) [75].
Pomalidomide (CC-4047) has also been shown to inhibit
PU.1 and therefore osteoclastogenesis [76]. Another study
reported that at a dose that induced apoptosis in MM cells,
IMiDs also showed an anti-osteoclast effect without affecting
Curr Hematol Malig Rep
osteoblasts [77]. It is increasingly clear that IMiDs are effec-
tive anti-MM agents with separate positive effects on the re-
lated bone disease [74, 78].
Surgery
Osteolytic lesions in MM rarely heal due to suppressed oste-
oblast function. Thus, surgical management of actual or
impending pathological fractures should be considered first
line [79]. Impending fracture is suggested by a loss of >50%
of cortical bone thickness. Orthopaedic consultation should be
sought for lesions in weight-bearing bones, bony compression
of the spinal cord and vertebral body instability, although sur-
gery is not frequently indicated due to the inherent radiosen-
sitivity of most MM [79]. Technically, the operative interven-
tion should allow full weight bearing post-operatively and not
rely upon healing of the fracture to achieve stability. Surgery
should be avoided in critically ill patients with an expected
duration of survival less than the time required for recovery
[80].
Radiotherapy
Radiotherapy has an established role in MM management and
is used in up to a third of patients during their disease course
[81]. Radiotherapy should be considered first-line therapy in
true solitary plasmacytomas, where it can be potentially cura-
tive, as well as in extramedullary masses and in spinal cord
compression [9]. It is also very useful as an adjunct to analge-
sia in the management of bone pain, with response rates of
more than 80% reported [81]. It should also be used as an
adjunct to operative fixation of actual and impending patho-
logical fractures. In these settings, radiotherapy promotes
bone healing and remineralisation, alleviates pain and reduces
analgesia use, improves functional status and reduces risk of
subsequent fractures. The limitation of radiotherapy is the
need to limit the involved field, especially prior to autologous
stem cell collection in eligible patients [81].
Balloon Kyphoplasty
Balloon kyphoplasty is a minimally invasive procedure that
should be considered in patients with symptomatic vertebral
compression fractures [6]. The procedure involves the percu-
taneous injection of bone cement (polymethylmethacrylate)
into the vertebral body after balloon inflation to expand the
collapsed vertebra. Kyphoplasty can be considered in patients
who are not fit for surgical intervention, and major complica-
tions are rare [82]. It is the procedure of choice to improve
quality of life, physical function and pain control in patients
with symptomatic vertebral compression fractures, with ben-
efits persisting for up to 2 years [82]. The role of simple
Curr Hematol Malig Rep
vertebroplasty is less clear due to paucity of data and a failure
to show benefit in osteoporosis trials [6].
Investigational Therapies
Investigational therapies are being developed in MM bone
disease [77]. Most therapies to date inhibit osteoclast function,
with none promoting bone formation through osteoblast stim-
ulation. BHQ880 is a first-in-class, fully human IgG1 anti-
DKK-1 monoclonal antibody, which increases osteoblast dif-
ferentiation and inhibits malignant plasma cell growth thus
mitigating against the development of osteolytic lesions
[83]. Recently, in a phase IB multicentre study of BHQ880
in combination with anti-MM therapy and ZOL in patients
with RRMM, BHQ880 was well tolerated and a trend toward
increased bone mineral density over time was observed.
However, the relative contribution of BHQ880 could not be
established due to concomitantly administered ZOL and anti-
MM therapy. Further research into the effects of BHQ880 in
MM is warranted [83, 84]. Sclerostin is a Wnt inhibitor, se-
creted by MM cells and found in high levels in patients with
advanced bone disease. Monoclonal antibodies against
sclerostin have been developed, including AMG785. This
agent has been shown to have biochemical anabolic effects
and increases bone mineral density, and the results of further
studies are awaited [77].
Conclusion
Survival outcomes for MM patients have substantially im-
proved over the past decade, but the disease remains incur-
able. Bone disease and its complications remain key aspects of
the management of patients, to not only maintain quality of
life but also improve survival. An increased understanding of
the biology of MM-related bone disease has not only facilitat-
ed the rational use of BPs but also the preclinical and clinical
development of new agents that inhibit osteoclastogenesis or
bone anabolic agents, such as anti-Dkk-1 and sclerostin.
Overall, a multimodal approach is required to MM bone
disease. Aggressive systemic therapy has beneficial effects on
MM bone disease itself, making it the cornerstone of therapy.
Bisphosphonates are obligatory in all MM patients and in
selected SMM patients. Radiotherapy or surgery should be
considered in patients with or at risk of pathological fractures.
Radiotherapy is particularly effective in controlling bone pain.
Kyphoplasty has a role in vertebral compression fractures.
Results of investigational therapies are awaited.
Finally, the continued development of biomarkers that re-
flect the activity of MM-related bone disease and predict treat-
ment response will represent a major advancement in the man-
agement of this common and potentially devastating
complication.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflicts of
interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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