Seminars in Cell and Developmental Biology 112 (2021) 49–58

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Seminars in Cell and Developmental Biology

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Review

Multiple myeloma—A painful disease of the bone marrow

Marta Diaz-delCastillo a, b, c, d, *, Andrew D. Chantry b, c, d, Michelle A. Lawson b, c,
Anne-Marie Heegaard a
a
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, Copenhagen Ø DK-2100, Denmark
b
Sheffield Myeloma Research Team, Department of Oncology and Metabolism, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK
c
Mellanby Centre for Bone Research, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK
d
Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK

A R T I C L E I N F O A B S T R A C T

Keywords: Multiple myeloma is a bone marrow neoplasia with an incidence of 6/100,000/year in Europe. While the disease
Multiple myeloma remains incurable, the development of novel treatments such as autologous stem cell transplantation, protea­
Bone marrow some inhibitors and monoclonal antibodies has led to an increasing subset of patients living with long-term
Quality of life
myeloma. However, more than two thirds of patients suffer from bone pain, often described as severe, and
Bone pain
knowledge on the pain mechanisms and its effect on their health-related quality of life (HRQoL) is limited. In this
review, we discuss the mechanisms of myeloma bone disease, the currently available anti-myeloma treatments
and the lessons learnt from clinical studies regarding HRQoL in myeloma patients. Moreover, we discuss the
mechanisms of cancer-induced bone pain and the knowledge that animal models of myeloma-induced bone pain
can provide to identify novel analgesic targets. To date, information regarding bone pain and HRQoL in myeloma
patients is still scarce and an effort should be made to use standardised questionnaires to assess patient-reported
outcomes that allow inter-study comparisons of the available clinical data.

US National Cancer Institute register were analysed, demonstrating that

1. Introduction
Multiple myeloma (MM) is a haematological condition characterised
by the abnormal proliferation of clonal, terminally differentiated B
lymphocytes in the bone marrow. The estimated worldwide incidence of
MM is 2 per 100,000 people [1] and up to 6 per 100,000 in Europe [2,3].
While the aetiology of the disease remains unknown, a genetic
component is suspected, as an increased risk among first-degree rela­
tives of myeloma patients has been identified [4–6]. Whether the spike
in prevalence among relatives has an underlying genetic cause or is a
consequence of shared environmental factors, such as exposure to toxic
chemicals, remains unclear. Several reports have suggested that expo­
sure to pesticides is correlated with higher risk of myeloma development
[7–11]. Similarly, it has been reported that clean-up workers of the
Chernobyl disaster [12] and survivors of the Nagasaki atomic bomb [13]
present a higher incidence of the disease than the general population,
suggesting a role for ionising radiation in myelomagenesis.
Age is an important risk factor for disease development. In a 2012
study on myeloma prevalence, data from over 40,000 patients from the
myeloma is a disease of the elderly, with the mean patient age at diag­
nosis being almost 70 years [14]. These data are in line with other Eu­
ropean multicentre studies showing mean age at diagnosis between 60
and 80 years [15–18]. While survival expectancy is lower in patients
above 65 years of age [14], autologous stem cell transplantation, a
common treatment approach among developed nations e.g. European
countries, Australia or North America [1], has shown encouraging re­
sults even in patients above 75 years of age [19].
1.1. Monoclonal gammopathy of undetermined significance (MGUS) and
MM: what is the difference?
Formal diagnosis of MM requires the detection of elevated mono­
clonal paraprotein (also known as monoclonal M protein) in serum or
urine, the presence of at least 10% myeloma cells in the bone marrow,
and the display of end-organ damage, often referred to as the CRAB
criteria: hypercalcemia, renal failure, anaemia, and bone lesions
[20,21]. The clinical presentation of the disease comprises a constella­
tion of symptoms, with bone pain, fatigue and infections being the main

* Corresponding author at: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160,
Copenhagen Ø DK-2100, Denmark.
E-mail address: marta.castillo@sund.ku.dk (M. Diaz-delCastillo).

https://doi.org/10.1016/j.semcdb.2020.10.006
Received 3 February 2020; Received in revised form 13 October 2020; Accepted 15 October 2020
Available online 4 November 2020
1084-9521/© 2020 Elsevier Ltd. All rights reserved.
M. Diaz-delCastillo et al. Seminars in Cell and Developmental Biology 112 (2021) 49–58

Nomenclature MMP Matrix metalloproteinase

NGF Nerve growth factor
ASIC Acid sensing ion channel NMDA N-methyl-D-aspartate
BDNF Brain derived nerve factor PGE2 Prostaglandin E
CCL Chemokine C-C motif Ligand PTHrP Parathyroid hormone-related protein
DKK-1 Dickkopf WNT signalling pathway inhibitor 1; RANKL Receptor activator of nuclear factor kappa-В ligand
HRQoL Health related quality of life SFRP Secreted frizzled-related protein
IL Interleukin TGFβ Transforming growth factor β
IMiDs Immunomodulatory drugs TrkA Tropomyosin receptor kinase A
QoL Quality of life TNF-α Tumour necrosis factor α
M-CSF Macrophage colony-stimulating factor TRPV1 Transient receptor potential cation channel subfamily V
MGUS Monoclonal gammopathy of undetermined significance member 1
MM Multiple myeloma V-ATPase Vacuolar-type H+ATPase

cause of initial physician consultation [22].
Interestingly, MM is preceded in virtually all patients by monoclonal
gammopathy of undetermined significance (MGUS) [23], an asymp­
tomatic disorder characterised by paraprotein levels > 3 g/dL and less
than 10% clonal myeloma cells in the bone marrow without end-organ
damage features [20]. In a prospective study, Landgren et al. [24]
screened a population of almost 78,000 people and identified a total of
71 patients who developed MM during the course of the study. By
measuring paraprotein levels in serum samples collected annually from
8 to 2 years before MM diagnosis, they found that all myeloma patients
had previously developed MGUS. The estimated risk of MGUS evolving
to MM or related disorders is approximately 1% per year, and remains
stable over time [25,26]. Several reports have indicated that the prev­
alence of MGUS ranges from 2% to 4% in the general population over 50
years of age, with men presenting a slightly higher prevalence than
women, and ethnical heterogeneity, with Black and Hispanic men pre­
senting higher prevalence of the disorder [26–28].
2. Myeloma-induced bone disease
Myeloma-induced bone disease, which is one of the main compli­
cations of MM, is characterised by severe bone loss and the development
of osteolytic lesions, which frequently result in fracture in myeloma
patients. Myeloma-induced bone disease occurs via several mechanisms,
leading to an imbalance in normal bone remodelling, where bone
resorption is dramatically increased and bone formation is suppressed
(Fig. 1). Myeloma cells can induce these changes to bone remodelling by
the secretion of factors that can directly modulate osteoclasts or osteo­
blasts. In addition, myeloma cells can indirectly cause alterations in
bone remodelling by stimulating other cells in the bone marrow
microenvironment to release bone modulating factors.
There are numerous osteoclast-activating factors secreted by
myeloma cells or released from the bone matrix following resorption,
including receptor activator of nuclear factor kappa-В ligand (RANKL)
[29,30], chemokine (C-C motif) ligands (CCL3 [31–34], CCL4 [32] and
CCL20 [34,35]), various interleukins (IL-1β [36,37], IL-3 [38], IL-6
[39,40] and IL-17 [36,41]), transforming growth factor beta (TGFβ)
[42–44] and tumour-necrosis factor alpha (TNFα) [45,46]. More
recently, this pool has expanded to include microRNA-21 (miR-21) [47],
X-box-binding protein 1 (XBP1) [48,49], B cell activating factor (BAFF)
[50,51], syndecan-1 [52], notch signalling mediators [53,54], osteo­
pontin (OPN) [55–57], sequestrome 1 (p62) [58] and C-X-C motif che­
mokine 12 (CXCL12) [59,60]. Many of the more recently identified
osteoclast-activating factors act as upstream or downstream mediators

Fig. 1. Pathophysiology of myeloma-induced

bone disease. Osteoclast-activating factors (e.g.
RANKL, CCLs, ILs, PTHrP, TGFß, MMPs, miR­
6 NAs, TNFα, M-CSF, PGE2) and osteoblast
inhibitory factors (e.g. DKK-1, SFRPs, ILs, acti­
1 vin A, TGFß) lead to an imbalance in normal
2 bone function in ~90% of myeloma patients
resulting in significant bone loss. These factors
are released by myeloma cells (1 and 2) and
5 other cells in the bone marrow microenviron­
ment (3, 4, 5 and 6) causing the upregulation of
osteoclastic bone resorption, whilst simulta­
neously inhibiting osteoblastic bone formation.
3 4 Myeloma cells also interact with osteoblasts or
bone lining cells leading to tumour cell
dormancy (7), which can result in drug resis­
tance, or later reactivation by osteoclasts.
Decreased Increased (Figure adapted from Green et al., 2019).
osteoblast osteoclast RANKL: Receptor activator of nuclear factor
formation
7 number kappa-В ligand; CCL: chemokine C-C motif
Bone lining ligand; IL: interleukin; PTHrP: parathyroid
cells hormone-related protein; TGFβ: Transforming
growth factor ß MMP: Matrix metalloproteinase;
miRNA: micro RNA; TNFα: Tumour Necrosis
Factor α M-CSF: Macrophage colony-stimulating
factor; PGE2: Prostaglandin E; DKK-1: Dickkopf
WNT signalling pathway inhibitor 1; SFRP:
secreted Frizzled-related protein.

50
M. Diaz-delCastillo et al.
of signalling pathways previously known to stimulate osteoclastogenesis
and osteolysis (e.g. RANKL), and offer new therapeutic targets for the
treatment of myeloma-induced bone disease.
Myeloma-induced bone disease is further exacerbated by the simul­
taneous release of osteoblast-inhibitory factors from myeloma cells and
the bone marrow microenvironment, which prevent osteoblast differ­
entiation and subsequently impair bone formation and repair. These
factors include dickoff-1 (DKK-1) [61,62], activin A [63–65], sclerostin
[66,67], secreted frizzled-related protein 2 (sFRP-2) [68,69], IL-3
[70,71], IL-7 [63,72,73] and hepatocyte growth factor (HGF) [74,75].
Moreover, bone resorption also causes release of TGFβ from the bone
matrix, which further increases myeloma-induced bone disease by pro­
moting osteoclastogenesis and preventing osteoblast progenitor differ­
entiation into mature osteoblasts. In addition, TGFβ acts on osteoblasts
and stromal cells to stimulate the release of pro-tumorigenic factors (e.g.
IL-6) [76], creating what is termed the ‘vicious cycle’ of bone destruc­
tion and myeloma tumour growth [77].
Myeloma cells can also interact directly with cells in the bone
marrow microenvironment leading to tumour cell dormancy. This can
result in drug-resistant populations of myeloma cells, which can later be
reactivated into proliferating tumour cells. Myeloma cell dormancy has
been demonstrated to be a reversible state that is switched ‘on’ by
engagement with bone-lining cells or osteoblasts, and switched ‘off’ by
osteoclastic bone resorption [78]. Therefore, increased osteoclastic bone
resorption is likely to lead to increased tumour cells and increased
myeloma-induced bone disease.
3. Current treatments for MM patients
Over the last twenty years major advances have been made in the
treatment of MM, leading to improved overall survival. Typically,
myeloma patients undergo a cycle of induction chemotherapy followed
by autologous stem cell transplantation, which induces a remission
phase of variable duration. In most cases, this phase is followed by
disease relapse, leading to the use of second line therapy and the
consequent treatment-free remission phase. This cycle generally con­
tinues, with each remission phase progressively shortening until anti-
myeloma drugs are unable to stop disease progression [79].
As discussed in Section 2, myeloma-induced bone disease is a
recurrent complication of MM. To reduce the risk of skeletal-related
events, patients are often treated with bisphosphonates (specific anti­
resorptive agents that promote osteoclast apoptosis) in addition to their
anti-myeloma treatments.
In the UK and Europe, induction therapy in the form of triplet regi­
mens is becoming the norm for newly diagnosed patients, typically
comprising a proteasome inhibitor (e.g. bortezomib or velcade), an
immune-modulatory imide drug (IMiD, e.g. thalidomide) and a corti­
costeroid (typically dexamethasone). This VTD regimen often involves
cycles that last 21 days, with four to six cycles typically given [80]. For
those patients considered ineligible for autologous stem cell trans­
plantation, either due to frailty or co-morbidity, induction chemo­
therapy triplets are favoured as they are slightly gentler in intensity and
typically comprise either velcade, the alkylating agent melphalan and
prednisolone (VMP) [81], or the alkylator cyclophosphamide, thalido­
mide and dexamethasone-attenuated regimen (CTDa) [82].
Second line therapy offered on evidence of relapse generally com­
prises re-induction with a regimen such as CTD when a second autolo­
gous stem cell transplantation is considered. Alternatively, the newly UK
National Institute of Clinical Excellence (NICE) approved regimen dar­
atumumab, a monoclonal antibody directed at CD38, in combination
with velcade and dexamethasone (DVd), offers an excellent long term re-
induction programme [83].
Third line therapy in the UK and frequently in Europe, often com­
prises the IMiD lenalidamide (Revlimid, Celgene) and dexamethasone,
plus or minus the novel oral proteasome inhibitor ixazomib [84]. This is
an attractive regimen being well tolerated and given indefinitely until
51
Seminars in Cell and Developmental Biology 112 (2021) 49–58
relapse, frequently suppressing disease for many years; further infor­
mation on the effect of these therapies on the patient’s quality of life
(QoL) will be discussed in Section 4 of this review.
Fourth line and subsequent lines of therapy include daratumumab
monotherapy (which is NICE approved in the UK for treatment as a
monotherapy in daratumumab-naïve patients [85]), the thalidomide
analogue pomalidamide and dexamethasone [86], as well as re-
treatment with velcade and dexamethasone with the addition of the
HDAC inhibitor panobinostat [87]. Other more hard hitting regimens, if
the patient is robust enough to tolerate them, include a triplet consisting
of the dual alkylator, purine analogue bendamustine, thalidomide and
dexamethasone [88].
Choice of fourth line and subsequent line therapies depend in part on
response to previous lines of therapy, as well as how robust the patient
remains in the face of progressive disease and whether there is a decline
in organ function. Eventually most patients succumb even though
multiple novel therapies are being introduced, often trialled first at these
latter stages of disease. It should also be noted that a cohort of patients
have myeloma for 20 or more years, tolerating multiple lines of treat­
ment, sometimes enjoying prolonged remission phases, and may even­
tually die of other pathologies. At present, the only therapy considered
capable of completely eliminating MM is allogeneic stem cell trans­
plantation. However, treatment-related mortality for patients enduring
this therapy is high, currently quoted around 15–20% and is therefore
reserved for high risk patients with aggressive disease [89].
4. Quality of life (QoL) in MM patients
MM patients have been shown to report more problems and symp­
toms than patients suffering from other haematological malignancies,
such as leukaemia or lymphoma [90], with more than two thirds of
patients being symptomatic at time of diagnosis [91]. Among the
symptoms that impair the patient’s health-related QoL (HRQoL), bone
pain and fatigue are the commonest, with pain affecting 51–61% of
patients [22,79,92,93], followed by sleepiness, hypo- or paraesthesia,
muscle cramps, constipation, oedema and insomnia [92].
As discussed in Section 3, induction chemotherapy followed by
autologous stem cell transplantation is the commonest treatment for
MM, and several studies have addressed its clinical efficacy and its effect
on HRQoL, showing that even during a stable plateau phase (in the
absence of active myeloma disease), bone aches and/or neuropathic
pain continues to affect 50% of patients, with 10% describing it as
“severe” [94]. Interestingly, both loss of weight and exposure to steroids
prior to autologous stem cell transplantation have been correlated with
worse physical function following treatment [95].
On the other hand, patients who are ineligible for a stem cell trans­
plant are often treated with a combination of chemotherapy and IMiDs.
A recent phase III clinical study evaluated the HRQoL of transplant
ineligible myeloma patients treated with melphalan-prednisolone
(chemotherapy) in combination with either the IMiDs thalidomide or
lenalidomide, as well as the effect of continuing treatment with the
IMiDs as maintenance therapy [96]. The results showed an improve­
ment in global QoL, future perspective and role and emotional func­
tioning, as well as a decrease in pain (regardless of the number of bone
lesions) for both IMiDs, while thalidomide caused peripheral neuropa­
thy in the majority of patients and lenalidomide caused diarrhoea.
In another study, QoL was assessed in patients with relapsed or re­
fractory myeloma who were treated with eight cycles of ixazomib-
thalidomide-dexamethasone, followed by 12 months maintenance
therapy with ixazomib [97]. A clinically significant improvement in
pain was observed following induction therapy, but a worsening of
neuropathy was also detected (neuropathy was present in 41% of pa­
tients at baseline, with a mean score of 22, which increased by 23 points
at the end of the study; scale 0–100, where 0 indicates less or no
symptom). Moreover, myeloma patients who went on maintenance
therapy showed non-significant improvements in HRQoL and pain,
M. Diaz-delCastillo et al. Seminars in Cell and Developmental Biology 112 (2021) 49–58

without worsening of side effects. These studies highlight the impor­
tance of addressing the effect of novel therapies on pain and QoL,
especially as it has been shown that gains in QoL can be more valuable
than increases in survival for elderly cancer patients [98].
To date, most studies addressing HRQoL are intervention studies in
which the effect of a novel drug or treatment is evaluated, like the ones
describe above. A 2017 systematic review on HRQoL in longitudinal
studies of myeloma patients concluded that newly diagnosed patients
are generally more symptomatic than those in relapse (possibly due to
the close monitoring of diagnosed patients by their clinicians), but
generally report an improvement in pain following first line treatment,
while pain levels were mostly unchanged during relapse treatment [99].
However, as the study highlights, information on pain and HRQoL in
patients who are not undergoing experimental cancer treatment (older
and frailer patients who are often not included in studies) is limited [99].
As the development of novel therapies is leading to a growing subset of
myeloma patients for whom the disease becomes long-lasting, under­
standing and improving the pain and consequently the HRQoL of these
patients is becoming increasingly important, and the use of standardised
tools to asses patient-reported outcomes, including pain, has been sug­
gested as the next step into personalised medicine for cancer patients
[100,101].
5. Pain in myeloma patients
5.1. Mechanisms of myeloma-induced bone pain
Despite the widespread use of animal models of MM over the last few
decades, which has significantly contributed towards our understanding
of the pathophysiology of the disease, there is a lack of preclinical pain
research of this condition. Animal models of myeloma mainly include
syngeneic models, in which myeloma cell lines are inoculated in
immunocompetent, strain-matched mice, and xenograft models, in
which human myeloma cell lines or patient-derived cells are inoculated
in immunosuppressed rodents [109].
To date, only a few publications have addressed myeloma-induced
bone pain in preclinical models, and most knowledge on cancer-
induced bone pain has been generated in models of bone metastases
(breast and prostate cancer) and osteosarcoma, revealing that cancer-
induced bone pain shares characteristics and mechanisms with inflam­
matory and neuropathic pain, but presents its own neurochemical
signature [110]. From these studies, three main drivers of cancer-
induced bone pain have been identified: (1) the activation of periph­
eral nerve fibres by pro-inflammatory agents and protons released in the
bone cancer microenvironment, (2) the damage, denervation or
sprouting of peripheral sensory nerves innervating the bone, and (3) the
deregulation of different proteins and molecular pathways in the dorsal
root ganglia and central nervous system. These findings are summarised
in Table 2.

Pain and fatigue are the main symptoms reported by myeloma pa­ 5.1.1. Peripheral mechanisms: activation of sensory fibres
tients, with the lower back and the arm/shoulder being the commonest As cancer cells proliferate in the bone, they often form a tumour mass
sites of pain reported by patients (Table 1); interestingly, average pain built of cancer, stromal and inflammatory cells, such as macrophages,
intensity seems to be maintained at the different phases of disease
progression and treatment. Myeloma pain can be classified into bone
pain as a consequence of myeloma-induced bone disease (including Table 2
skeletal-related events such as pathological fractures), procedural pain Summary of the proposed peripheral and central mechanisms of bone pain in
(as patients are exposed to a range of invasive and non-invasive pro­ multiple myeloma. NGF = nerve growth factor.
cedures) or neuropathic pain, often caused by treatment-related toxicity Proposed mechanisms of Animal model Reference
[102]. Chemotherapy-induced peripheral neuropathy is characterised myeloma-induced bone
by numbness, tingling and pain in a stocking/glove pattern, and can be pain

caused by neurotoxicity derived from chemotherapeutic drugs, as well Peripheral Activation of afferent Intratibial Hiasa et al.
as proteasome inhibitors such as bortezomib or IMiDs like thalidomide nociceptors due to innoculation of JJN3 [117]
tumour-induced cells in C57BL/6
[103,104]. The grade of neuropathy depends on the drug, dose and
acidification of neuronal SCID mice (xenograft
duration of the treatment, and it is more prevalent in myeloma patients microenvironment. model).
with baseline neuropathy [105]. Chemotherapy-induced peripheral Tumour-induced
neuropathy can often resolve [105] or be treated with calcium channel sprouting of sensory nerve
blockers such as gabapentin or pregabalin [106]; however, poly­ fibres.
Tumour-induced injury of Intrafemoral Diaz-
neuropathy remains the commonest treatment-related adverse effect
sensory nerve fibres. innoculation of delCastillo
[79]. 5TGM1-GFP cells in et al. [129]
Myeloma-induced bone pain is generally treated following the syngeneic C57BL/
analgesic ladder for the management of cancer pain proposed by the KaLwRijHsd mice.
Increased NGF production Intravenous Olechnowicz
World Health Organization [107]. This three-step ladder recommends
by bone marrow stromal inoculation of et al. [128]
the use of non-steroidal anti-inflammatory drugs (NSAIDs) for the cells. 5TGM1-GFP cells in
treatment of mild pain, followed by increasingly strong opioids as the Central Spinal microglia syngeneic C57BL/
pain progresses. The use of bisphosphonates is also recommended for the activation. KaLwRijHsd mice.
treatment of skeletal disease derived pain, even though their analgesic Spinal astrocyte
activation.
effect on bone pain remains to be firmly established [108].

Table 1
Pain prevalence and average pain intensity in different body sites in myeloma patients during disease progression. Average pain intensity reported in the standardised
QLQ-MY20 questionnaire, based on the following scale: 1 = “Not at all”, 2 = “A little”, 3 = “Quite a bit” and 4 = “Very much”. The average pain intensity at diagnosis
reported in this table was calculated by extrapolating the data published by Mols et al. [153] Data on average pain intensity during/on completion of first line
treatment and at advanced but stable disease phases were extracted from Cocks et al. [154] and Boland et al. [94], respectively.
Pain

Bone Back Hip Arm/ shoulder Chest

At diagnosis [138] Presence of pain (% patients) 52.7 61.3 34.6 47.6 16.54
Average pain intensity (Mean ± SD) 1.9 ± 1.0 2.0 ± 1.0 1.5 ± 0.8 1.7 ± 0.8 1.2 ± 0.5
During or on completion of first-line treatment [139] Average pain intensity (Mean ± SD) 2.1 ± 0.9 2.0 ± 0.9 1.6 ± 0.8 1.5 ± 0.7 1.3 ± 0.6
At advanced (> 2 treatment lines), stable phase [94] Average pain intensity (Mean ± SD) 2.4 ± 1.0 2.0 ± 1.0 1.6 ± 1.0 1.2 ± 0.4 2.2 ± 1.0

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M. Diaz-delCastillo et al.
neutrophils, leucocytes and mast cells [111,112]. Often the tumour cells
release neurotrophines i.e. nerve growth factor (NGF) and brain-derived
neurotrophic factor (BDNF), which can then bind to their receptors in
the macrophages, causing the release of pro-inflammatory cytokines (e.
g. TNFα, IL6 and IL1ß) and other proalgesic inflammatory mediators (e.
g. prostaglandin E) that can directly sensitise the sensory primary af­
ferents innervating the bone [112].
As discussed in Section 2 of this review, cancer cells also cause al­
terations in bone remodelling process, and in MM an increase in oste­
oclastic bone resorption and a suppression of osteoblastic bone
formation [113], resulting in osteolytic lesion development [114]. As
both osteoclasts and cancer cells liberate protons and lactate, the bone
microenvironment can become pathologically acidic, possibly inducing
the activation of acid-sensing nociceptors such as acid-sensing ion
channels (ASICs) or transient receptor potential cation channel sub­
family member 1 (TRPV1) [115], resulting in the depolarisation and
sensitisation of sensory fibres and consequent generation of nociception.
In 2007, Nagae et al. showed that ASIC1a, ASIC1b and TRVP1 are
transcriptionally up-regulated in the ipsilateral dorsal root ganglia of a
rat model of painful breast cancer bone metastases, parallel to the
development of pain-like behaviour [116]. Moreover, they showed that
daily systemic treatment with the bisphosphonate zolendronic acid was
analgesic, and reduced the mRNA expression of these nociceptors.
Similarly, a xenograft mouse model of myeloma-induced bone pain
displayed a significant improvement in pain-like behaviours following
the inhibition of either the vacuolar-type H+ ATPase (V-ATPase) or
ASIC3 [117]. Moreover, these treatments also reduced the over­
expression of neuronal excitation markers suggestive of nociception,
such as phosphorylated ERK and cAMP response element binding pro­
tein (pCREB) [117]. In this model, bisphosphonate treatment also
ameliorated myeloma-induced bone pain, and the analgesic effect was
potentiated when combined with the V-ATPase inhibitor. Based on these
data, the authors propose that the acidification of the tumour micro­
environment caused by proton pumps located in myeloma cells may be
one of the mechanisms involved in myeloma-induced bone pain
development.
5.1.2. Peripheral mechanisms: disturbances of sensory fibres
Under physiological conditions, sympathetic and sensory neurons
innervate all bone compartments: mineralised bone, bone marrow and
periosteum. While the density of sympathetic fibres is clearly higher in
cortical pores [118], the ratio of sensory neurons in mineralised bone,
bone marrow and periosteum has been described as 0.1:2:100 (density,
mm/mm3), respectively [119]. Interestingly, mouse studies of bone
innervation have shown a decrease in sympathetic innervation of the
cortical bone with aging, while the density of sensory neurons remained
unchanged, suggesting that nociceptors transmitting bone pain are
intact in the elderly [120]. Most sensory neurons innervating the adult
bone express tropomyosin receptor kinase A (TrkA+) [119] and can be
classified as Aδ or peptide-rich C-fibres: Aδ fibres are fast-conducting,
myelinated neurons that convey acute, localised noxious stimuli, while
C-fibres are small and unmyelinated, transmitting slow, poorly localised
noxious stimuli [121,122]. The sensory fibres innervating the bone are
often considered as silent nociceptors, which can be activated by me­
chanical, acidic or chemical stimuli to convey the nociceptive signal. It is
generally believed that the Aδ fibres transmit the fast, acute pain upon
activation (e.g. bone fracture), while the C-fibres are responsible for the
dull, constant, secondary bone pain [122].
In the last two decades, several reports have acknowledged an in­
crease in the density of TrkA+ nerve fibres (sprouting) innervating the
periosteum of cancer-bearing bones in rodent models of painful breast
[123] and prostate [124] cancer metastases to the bone, as well as in the
NCTC2472 mouse model of osteosarcoma [125]. In all cases, treatment
with an antibody targeting NGF (ligand of the TrkA receptor) attenuated
nerve sprouting and induced preventive treatment-induced analgesia.
Similarly, clinical trials with tanezumab (monoclonal antibody targeting
53
Seminars in Cell and Developmental Biology 112 (2021) 49–58
NGF) have shown promising preliminary results [126]. These data
suggest that an important driver in cancer-induced bone pain is the
disorganised, pathological sprouting of sensory and sympathetic nerve
fibres innervating the periosteum. Paradoxically, tumour-induced nerve
damage has also been reported in the mouse model of osteosarcoma as
an important mechanism of bone pain [127]. It seems, thus, that both
nerve sprouting and nerve damage may be caused by bone cancer and
involved in cancer-induced bone pain.
In 2017, Hiasa et al. [117] proposed that myeloma cells populating
the bone marrow express proton pumps, which induce an acidification
of the tumour microenvironment, as discussed in Section 5.1.1. Their
research suggested that such acidification of the bone marrow could, in
turn, stimulate nerve sprouting and activate the acid-sensing noci­
ceptors of the sensory neurons, consequently causing nociception.
Immunohistological examination of the femurs of myeloma-bearing
mice showed increased density of calcitonin gene-related peptide
(CGRP)-positive neurons parallel to disease progression, and inhibition
of both the V-ATPase or ASIC3 was efficient in reducing pain-like be­
haviours in these mice, as well as CGRP sprouting and overexpression of
excitation neuronal markers in the dorsal root ganglia.
Another recent publication [128] has studied pain-related mecha­
nisms in a systemic, immunocompetent mouse model of myeloma,
suggesting that factors released by myeloma cells in the marrow induce
the production of NGF by bone marrow stromal cells populating the
tumour niche, and that NGF may also mediate myeloma-induced bone
pain.
Our group has evaluated nociception in a syngeneic mouse model of
myeloma established by direct intrafemoral inoculation of a murine
myeloma cell line (5TGM1) in strain-matched immunocompetent BKAL
mice [129]. These mice presented high levels of systemic serum para­
protein and developed osteolytic lesions, in agreement with the clinical
presentation of the disease. Moreover, the mice presented pain-related
behaviours over time, which could be completely reversed by systemic
morphine administration. Biweekly bisphosphonate treatment in these
mice prevented the development of osteolytic lesions, increased survival
and decreased pain-like behaviours, though the treatment did not fully
reverse the nociceptive phenotype. In the clinic, conflicting data has
been reported regarding the analgesic effect of bisphosphonate treat­
ment on myeloma-induced bone pain; while several studies have shown
an analgesic effect, data from double-blinded randomised clinical trials
have shown no clinical significance [108]. Interestingly, immunohisto­
chemical characterisation of the sensory neurons in the myeloma-
bearing femurs of these mice revealed complete bone marrow dener­
vation at end-stage disease, suggesting alternative pathways contrib­
uting to the development of myeloma-induced bone pain, which may
arise from a combination of osteolytic lesion development and periph­
eral nerve injury (Fig. 2). However, the timeline of this myeloma-
induced peripheral nerve injury and how it might impact nociception
is unknown. As mentioned above, tumour-induced nerve damage of the
bone marrow and mineralised bone was reported in a mouse model of
osteosarcoma-induced bone pain. In this model, nerve damage was
accompanied by an increase in activating transcription factor 3 (ATF3)
and the neuropeptide galanin in the cell bodies of afferent sensory
neurons innervating the femur [127]. This model also showed increased
glial fibrillary acidic protein (GFAP) and macrophage infiltration and
activation in the dorsal root ganglia, all of it indicative of neuropathic
mechanisms contributing to osteosarcoma-induced bone pain following
tumour-induced bone denervation [127]; it remains to be elucidated
whether these neuropathic features also play a role in myeloma-induced
bone pain.
The observation of myeloma-induced bone denervation is in contrast
to the results by Hiasa et al. [117] who showed myeloma-induced nerve
sprouting as a main driver for myeloma-induce bone pain. These con­
tradictory data may be explained by the different animal models
(immunosuppressed vs. immunocompetent) or disease time-course, and
highlight the challenges of using animal models in pain research.
M. Diaz-delCastillo et al.
GAP-43
am
Sha
20µm
MM
20µm
Fig. 2. Myeloma induces disturbances in bone innervation. Representative pictures of the bone marrow innervation of sham and myeloma-bearing mice displaying
pain-related behaviours. Adapted from Diaz-delCastillo et al. [129]. GAP-43: Growth-associated protein 43; TH: Tyrosine Hydroxylase; CGRP: Calcitonin gene-
related peptide.
Importantly, none of the studies described above report on the effect of
multiple myeloma on periosteal bone innervation. As discussed, peri­
osteal nerve sprouting has been implicated in nociception in several
rodent models of painful bone disorders including models of cancer-
induced bone pain [123–125]. Thus, a further characterisation of the
effect of myeloma on periosteal bone innervation is warranted.
5.1.3. Central mechanisms: role of microglia and astrocytes
Upon noxious activation of afferent sensory neurons innervating the
bone, the nociceptive signal is transmitted towards the dorsal horn of the
spinal cord, where it is integrated and further projected towards
suprathalamic brain structures. This extra modulation in the central
nervous system probably explains why there is no direct correlation
between the number and volume of bone tumours and the pain levels
reported by cancer patients [110,130].
Cancer-induced bone pain is often characterised by changes in the
expression of different factors in spinal cord and brain that lead to
hyperalgesia (perception of excessive pain following a noxious stimulus)
and allodynia (perception of pain following a non-noxious stimulus).
Rodent models of cancer-induced bone pain have shown multiple
neurochemical changes in the dorsal horn of the spinal cord, mainly the
upregulation of c-Fos [131,132] and dynorphin [127,132], as well as
hypertrophy of astrocytes [132,133], which may secrete cytokines and
other proalgesic molecules that in turn sensitise spinal neurons involved
in the processing of noxious signals. Similarly, an increase in ionised
calcium binding adaptor molecule 1 (Iba1) and glial fibrillary acidic
protein (GFAP), specific markers of microglia/macrophages and astro­
cytes, respectively, has been detected in dorsal horn of the spinal cords
of myeloma-bearing mice, indicating that myeloma may induce spinal
glia activation [128]. Moreover, activation of glial cells in suprathalamic
brain centres involved in pain signalling, such as the rostral ventrome­
dial medulla, has also been described in cancer-induced bone pain
[134].
An important phenomenon in chronic pain is the increased
54
Seminars in Cell and Developmental Biology 112 (2021) 49–58
TH CGRP
20µm 20µm
20µm 20µm
excitability of spinal neurons, known as central sensitisation, in which
low-stimulus nociceptive inputs result in increased amplitude and
duration (hyperalgesia). Central sensitisation is, to a great extent,
mediated by N-methyl-D-aspartate (NMDA) receptors [135], and their
involvement in the maintenance of cancer-induced bone pain has been
described [136,137]. However, no studies on NMDA-mediated central
sensitisation in myeloma-induced bone pain are available to date. Taken
together, it seems that diverse mechanisms may be involved in driving
myeloma-induced bone pain, including bone disturbances, changes in
the peripheral nervous system and central mechanisms that remain
undiscovered.
5.2. Mechanisms of treatment-derived pain in multiple myeloma
As discussed in Section 3, multiple myeloma patients are typically
treated with triple regimens containing chemotherapy agents.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common
complication in cancer survivors that significantly impairs their quality
of life [138], with 68% patients reporting symptoms within the first
month following chemotherapy treatment, and 30% reporting persistent
symptoms after 6 months of end of chemotherapy [139]. Clinical CIPN
frequently manifests as decreased touch perception, which is believed to
be caused by loss of epidermal nerve fibres (affecting both Aβ, Aδ and C-
fibres), as well as Meissner’s corpuscles [140].
To better understand the underlying pathophysiology of CIPN, many
animal models have been developed by systemic administration of the
specific chemotherapeutic agents (platinum compounds such as
cisplatin or oxiplatin, taxanes like paclitaxel or docetaxel, vinca alka­
loids like vinscritine, proteasome inhibitors, etc.) to mouse or rat [141].
These models generally display mechanical allodynia and hyperalgesia,
and occasionally thermal alterations, providing a useful insight into the
nociceptive mechanisms of CIPN and the potential analgesics for its
treatment [141].
In the case of multiple myeloma, patients often receive the first-
M. Diaz-delCastillo et al.
generation proteasome inhibitor bortezomib, and it has been reported
that the incidence of sensory peripheral neuropathy in this patient
population ranges from 8.4% to 80.5% [142]. Animal models of
bortezomib-induced peripheral neuropathy include mice displaying
disturbed thermal sensitivity [143], and rat models displaying me­
chanical and cold allodynia, but no thermal hyperalgesia [144,145]. The
differences in behavioural outcomes across models may be explained by
the myriad of bortezomib-induced alterations that have been identified.
These include a reduction in amplitude of sensory action potentials
[143], axonal degeneration [145,146], nociceptor sensitisation as a
result of decreased astrocyte-mediated glutamate clearance [147,148]
and increased TRPV1 expression in the spinal cord and cell bodies of
sensory neurons [149]. Moreover, bortezomib-induced damage of
mitochondria [150] and mRNA processing in the cell bodies of primary
sensory neurons have also been identified [151]. The complicated and
additive mechanisms by which chemotherapeutic agents induce CIPN
have hindered the development of effective analgesic options for this
patient population; however, it is expected that the next generations of
proteasome inhibitors will induce significantly less side effects [152].
6. Conclusion
Multiple myeloma is a highly heterogeneous disease that causes bone
pain in the majority of patients. While current advances in the field have
led to increased survival, further research is needed to understand the
aetiology of the disease and its symptoms, especially in regards to bone
pain. Animal models of MM and myeloma-induced bone pain can be a
useful tool to identify the underlying mechanisms of bone pain and
potential novel targets for its treatment.
Conflicts of interest
The authors report no conflicts of interest.
Acknowledgements
This work was supported by the IMK Fonden. The funding source was
not involved in planning, writing or submitting this manuscript.
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