Myeloma bone disease: Managementnssg.oxford-haematology.org.uk/.../myeloma-bone... · Thames Valley Cancer Network – Update in Myeloma and Plasma Cell Dyscrasias • In May 1840,

Dr Andrew Chantry Senior Clinical Lecturer in Haematology, Dept of Oncology/

Honorary Consultant in Haematology, Sheffield Teaching Hospitals Foundation Trust

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Sheffield Myeloma Research Team

Dept of Oncology

Myeloma bone disease: Management

Mon 15th September Thames Valley Cancer Network – Update in Myeloma and Plasma Cell

Dyscrasias

• In May 1840, Sarah Newbury experienced severe back pain while stooping and a strange sensation in her right leg. • She was given an infusion of orange peel and a rhubarb pill. • Sections of the bones revealed ‘a red grumous matter’; the red matter was examined by Dr Solly and Mr Birkett of Guy’s Hospital; the majority of the nucleated cells had a clear, oval outline and one or rarely two bright central nucleoli

Calico Hills Burial #2 (AD 2-900)

‘Mollities Ossium’ (Dr Samuel Solly 1846)

Prehistoric multiple myeloma – Red Indian artefacts

Sowell Mound Skull (approx AD 610)




Morse, D et al, NY Acad Med, 1974

Normal

Myeloma ‘pepper

pot skull’

Approximately 60% of pts with myeloma present with evidence of osteolytic bone disease; 80-90% pts with myeloma have lytic bone disease at some stage of their disease (Coleman

1997; Kariyawasan et al. 2007) Treatment for myeloma bone disease is currently inadequate

Devastating consequences of myeloma bone disease

If it wasn’t fractured before…

Fracture risk 16x higher than expected (Melton et al 2005)

Imaging techniques • The skeletal survey remains the screening technique of choice at diagnosis • Computerized tomography (CT) scanning or magnetic resonance imaging (MRI) should be

used to clarify the significance of ambiguous plain radiographic findings, such as equivocal lytic lesions, especially in parts of the skeleton that are difficult to visualize on plain radiographs, such as ribs, sternum and scapulae.

• Urgent MRI is the diagnostic procedure of choice to assess suspected cord compression in myeloma patients with or without vertebral collapse (Grade B recommendation; level IIB evidence). Urgent CT scanning is an alternative, when MRI is unavailable, intolerable or contraindicated (Grade B recommendation; level III evidence).

• CT or MRI is indicated to delineate the nature and extent of soft tissue masses and where appropriate, tissue biopsy maybe guided by CT scanning (GradeB recommendation; level IIB evidence).

• There is insufficient evidence to recommend the routine use of positron-emission tomography (PET) or 99mTechnetium sestamibi (MIBI) imaging. Either technique may be useful in selected cases for clarification of previous imaging findings preferably within the context of a clinical trial.

• Bone scintigraphy has no place in the routine staging of myeloma. • Routine assessment of bone mineral density cannot be recommended, owing to the

methodological difficulties of the technique and the universal use of bisphosphonates in symptomatic myeloma patients

Pre-osteoclast

CFU-GM

Osteoclasts

Bone

+

+

+

Mesenchymal Stem Cells

Osteoprogenitor

Osteoblasts

-

-

-

• RANKL

• MIP 1-α

• Il-3

Osteoclast activating factors

Osteoblast inhibitory factors • Dkk-1

• sFRP-3

• HGF

• TGF-β1

Mechanisms of myeloma bone disease

These targets validated in our studies; working towards personalised therapy

Plasma cells

Normal

Myeloma

The result – bone is destroyed

Myeloma – close up

+

+

+

Pre-osteoclast

CFU-GM

Osteoclasts

Bone

Mesenchymal stem cells

-

-

Plasma cells

Bisphosphonates – for all patients with symptomatic myeloma

• Clodronate, zoledronic acid or pamidronate; Zol is Tx of choice based on SRE’s but less ONJ c clodronate;

• Calcium supplementation – current guidelines recommend for zoledronic acid but not for clodronate; in reality, practice varies; pragmatic approach may be to precribe Ca supplements as per the SPC for zoledronic acid but to monitor Ca levels.

• Attend to dentition prior to commencing bisphosphonates • Duration of treatment with bisphosphonates remains contentious; clinician

discretion; given the modest survival advantage reported in MMIX in patients treated with zol, now a rationale for indefinate Tx

• The serum creatinine should be checked before each dose of pamidronate or zoledronic acid, and patients should be monitored every three to six months for albuminuria

• The drugs should be stopped in patients who show renal deterioration while receiving a bisphosphonate, but they may be resumed once the problem is identified and resolved.

The UK MRC Myeloma IX trial has shown that zoledronic acid is superior to

clodronate (Morgan et al, Lancet, 2010)

• reduction of myeloma related skeletal events (27% vs 35%)

• but also in its association with a survival advantage.

• Even after a relatively short median follow-up of 3.7 years, patients receiving

zoledronic acid survive 5.5 months longer than those receiving clodronate and 10

months in patients with bone disease at diagnosis.

• Progression free survival is also increased by 2 months (19.5 months vs 17.5

months) (Morgan, Davies et al. 2010).

• Incidence of ONJ – zoledronic acid 4%, clodronate <1%

Pamidronate

(Aredia)

O

O-

O-

O-

O-

O P C P

OH

(CH2)2

NH2

O

O- O-

O

OH

O- O-

P C P

CH2

N

N

Clodronate

(Bonefos, Loron)

O

O-

O-

O-

O-

O P C P

Cl

Cl

Zoledronate

(Zometa, Aclasta)

Survival advantages of zoledronic acid – caveats (Rajkumar editorial, Lancet 2010)

• in most countries other than the UK, the alternative bisphosphonate to zoledronic acid is pamidronate (10x less expensive than zoledronic acid) not clodronate and pamidronate, and has not been associated with a survival disadvantage and may also have a lower incidence of ONJ.

• Unclear whether patients without bone disease at presentation do better or not.

• Most survival benefit appears to be derived early ie within the first 4 months of treatment – important but, mortality in this cohort at this juncture is quoted at 8%. This compares less favourably with mortality at this juncture in patients treated with lenalidomide or Bortezomib which is quoted as 1% or less.

• Median duration of treatment with zoledronic acid is 12 months; given most benefit appears to be gained early, he suggests that this should not be used to justify indefinite treatment with zoledronic acid.

Potential anti tumour mechanisms of zoledronic acid

1. Preservation of boney barriers (Fleisch H 2001) 2. Seed and soil concept – attenuation of the fertile environment ie less TGF-β, ILGF

liberated from resorbed bone (Mundy and Yoneda 1995) 3. Disruption of cell adhesion to mineralised surfaces (van der Plujm et al 1996) 4. Pro-apoptotic effects either via inhibition of the mavelonate pathway for the

nitrogen containg bisphosphonates (Shipman et al 1998) or the accumulation of non-hydrolysable ATP derivatives for non-nitrogen containing bisphosphonates (Fleisch H 2001).

5. Unspecified anti-angiogenic effects in mouse models (Croucher et al 2003) 6. Enhanced γδ T-cell mediated immunosurveillance (Kunzmann et al, 2000) 7. Potential synergies - including doxorubicin, paclitaxel and cyclophosphamide(Vogt

et al. 2004; Neville-Webbe et al. 2005; Neville-Webbe et al 2006). Most recently, sequential administration of doxorubicin followed 24 hours later by zoledronic acid has been shown to decrease tumour burden in a mouse model of breast cancer (Ottewell et al 2009).

Osteonecrosis of the jaw – incidence varies from 2 -10%

Stage 3

BRONJ Stage Description

At risk No apparent exposed bone in oral or IV BP patients

Stage 1 Exposed/necrotic bone with no signs of infection

Stage 2 Exposed/necrotic bone with signs

of infection (pain, swelling etc)

Stage 3

Exposed/necrotic bone with signs of infection & either pathological

fracture, extraoral fistula or osteolysis

Zoledronic acid – prescribing issues

• Duration of treatment with bisphosphonates remains contentious; clinician discretion; given the modest survival advantage reported in MMIX in patients treated with zol, now a rationale for indefinate Tx

• Interupting therapy for essential dental work – six weeks before, consider re-starting once healing

complete.

• Calcium supplementation – current guidelines recommend for zoledronic acid but not for clodronate; in reality, practice varies; pragmatic approach may be to precribe Ca supplements as per the SPC for zoledronic acid but to monitor Ca levels.

• Renal impairment – 12% of patients with MM, breast cancer or prostate cancer show renal

deterioration after 24/12 of treatment but nb no difference in renal function between zoledronic acid and clodronate in the Myeloma IX cohort.

Radiotherapy, vertebroplasty and kyphoplasty

Recommendations • Local radiotherapy is helpful for pain control; a dose of 8 Gy single fraction is recommended (Grade C, level III) (may also promote healing of the fracture site) • Long bone fractures require stabilisation and subsequent radiotherapy; a dose of 8 Gy single fraction is recommended (Grade C, level III) Where large lytic lesions may cause skeletal instability an orthopaedic opinion should be sought and pre-emptive surgery considered in selected patients. Specialised clinical interventions for pain associated with spinal fractures including vertebroplasty and kyphoplasty.

Spinal cord compression – up to 5% of all pts with myeloma at some stage (Kyle et al 2003)

Spinal cord compression (BCSH Guidelines Recommendations)

- suspect if rapid onset of sensory loss, paraesthesia, sphincter disturbance, limb weakness or walking difficult; commence dexamethasone 40mg po od • Urgent MRI should be performed and neurosurgical or spinal surgical / clinical oncology consultation obtained (Grade C, level IV) • Local radiotherapy is the treatment of choice for non-bony lesions and should be commenced as soon as is possible, preferably within 24 hours of the diagnosis. A dose of 30Gy in 10 fractions is recommended (Grade B; level IIb) • Surgery is recommended for emergency decompression in the setting of bony compression and/or to stabilize the spine (Grade C, level IV) • If cord compression is a presenting symptom, it is important to concurrently pursue a rapid diagnosis and to institute systemic therapy as soon as possible (Grade C, level IV) • Vertebroplasty – performed under local anaesthesia • Kyphoplasty - requires gerneral anaesthesia; optimal only soon after vertebral collapse ie must be re-expandible

Solitary plasmacytoma of bone (SBP)

• should be diagnosed by tissue biopsy by histopathologists • Monoclonality and/or an aberrant plasma cell phenotype should be demonstrated with useful markers being CD19, CD56, CD27, CD117 and cyclin D1 (Rawstom et al, 2008); (if aberrant phenotype confirmed, should pt recieve systemic therapy?) • median age 60, M:F 2:1, • 51% myeloma at 5 yrs, 72% myeloma at 10 yrs; median time to myeloma 21/12 • 75% of pts have an M-protein in blood or urine, usually<10g/l • Mandatory Invx – FBC, U&E, Ca, sIgs, serum and urine EP and IF, SFLC, skeletal survey, MRI of spine and pelvis, BMA&T • Imaging - CT best for boney lesions lesions, MRI best for soft tissue lesions, PET CT can potentially identify active lesions Mx of solitary bone plasmacytoma • radical DXT encompassing the tumour volume shown on MRI • Consider Sx and DXT if structural instability/cord compression • CT planned, GTV-PTV margin 2cm • No evidence to treat whole bones • <5cm 40Gy in 20 fractions (Gy=J/kg) • >5cm 50Gy in 25 fractions

Extramedullary plasmacytoma (EP)

• soft tissue infiltration by clonal plasma cells - less common than SBP (SBP:EP 80:20%) • 80% head and neck especially the upper respiratory tract • Usually remain localised and progression to myeloma is uncommon • In contrast to SBP, a monoclonal protein is detected in <25% of pts with EP • EP must be distinguished from reactive plasma cells and lymphoma; must be demonstrated that the infiltrate consists entirely of plasma cells with no B-cell component • In this regard CD138, MUM1/IRF4, CD20 and PAX5 are the most useful markers although nb CD20 and PAX5 are sometimes expressed in plasma cell malignancies • Monoclonality and/or an aberrant plasma cell phenotype should be demonstrated with useful markers being CD19, CD56, CD27, CD117 and cyclin D1 • Diagnosis must be made by a histopathologist • Treatment - radical radiotherapy encompassing the primary tumour with a margin of at least 2cm, include nearby nodes, <5cm 40Gy in 20 fractions (Gy=J/kg), >5cm 50Gy in 25 fractions

B

C

A

E

F

D ii iii i

ii iii i

ii iii i

I G H

**

*

**

**

*

**

*

** *

** *

Naive

JJN3

U266

Murine models of myeloma bone disease (xenograft)

• 1% of elderly C57BL/KaLwRij mice spontaneously develop a distinctive myeloma like disease.

• This gave rise to the 5T series of myeloma models (5T2, 5T33, 5TGM1).

• A paraprotein is detectable after 8 weeks and mice subsequently develop characteristic osteolytic disease.

5T2MM Naive

Naive

5T2MM

0

1

2

3

naïve 5T2MM

N.O

c/B

S (/m

m)

p<0.001

Naive

5T2MM 0

5

10

15

20

25

naïve 5T2MM

N.O

b (/m

m)

p<0.05

The 5TMM series of mouse myeloma models

Analysis of tumour burden • Flow cytometry

• CD138 colonies

• MP Microscopy

• Serum paraprotein

R2R2R2

500 µm Bone

GFP DID

Inte

nsity

Analysis of bone parameters • Bone marker serum levels

• Static histomorphometry

• Dynamic histomorphometry

• Micro-CT in vivo scanner to

determine bone volume and structure, no. of lesions

• BioDent reference point indenter

• Three point stressing test

Naϊve

5T2MM + veh

0

200

400

600

800

1000

4 6 8 10 12 14 16 18 Age/Weeks

P1N

P (n

g/m

l)

0 5

10 15 20 25 30 35 40

4 6 8 10 12 14 16 18 Age/Weeks

TRA

P (U

/L)

Pre-osteoblast

The Wnt signalling pathway and myeloma bone disease

Dkk-1/Sost DC1 sFRP-3

Wnt

No differentiation

• Dkk-1 over-expressed in most but not all myeloma cells (Tian et al 2003, Giuliani et al 2005).

• Other soluble Wnt antagonists also implicated (sFRP2 and sFRP3) (Oshima et al 2005; Chantry et al 2009)

• Anti-Dkk-1 prevents bone disease in the experimental models of myeloma (Yaccoby et al 2007; Chantry et al 2009)

• LiCl, as an inhibitor of glycogen synthase kinase 3β, and activator of wnt signaling prevents myeloma bone disease (Edwards et al 2007).

Anti Dkk-1 prevents 5T2MM induced decreases in osteoblast number and function

5T2MM+vehicle Naive 5T2MM+Anti Dkk-1

+5T2MM Na ï ve + Veh +AntiDkk1 0

5

10

15

20

25

30 p<0.001 p<0.001

Ob.

N (/

mm

)

Osteoblast No

+5T2MM Na ï ve + Veh +AntiDkk1 0

5

10

15

20

25

30

Ob.

N (/

mm

)

0 5

10 15 20 25 30 35

Ob.

S/BS

(%)

+5T2MM + Veh +AntiDkk1

+5T2MM + Veh +AntiDkk1 Na ï ve Na ï ve

p<0.001 p<0.001

Osteoblast Surface

Chantry AD, Buckle CH et al; JBMR, March 2009

Inhibiting Dkk1 prevents bone disease in myeloma

Naive 5T2MM 5T2MM + anti Dkk-1

Naive 5T2MM + anti Dkk-1 5T2MM

Lesion Number

+ 5T2MMNaïve Veh AntiDkk10

102030405060

p<0.05

Num

ber

p<0.05Lesion Number

+ 5T2MMNaïve Veh AntiDkk10

102030405060

p<0.05

Num

ber

p<0.05

0

4

8

12

BV/T

V%

+ 5T2MM Naïve Veh AntiDkk-1

Trabecular Volume

Naïve

p<0.05 p<0.05

Naive

Multiple Myeloma

Chantry et al, JBMR 2009

Multiple Myeloma + anti Dkk-1

Smad2/3 Smad4

• Activins are members of the transforming growth factor beta (TGF-β) superfamily.

• Activins and inhibins were first identified as important regulators of pituitary follicle stimulating hormone release.

• Also play important roles in embryology, wound healing and tissue homeostasis • Activin has recently been shown to inhibit osteoblast differentiation.

ALK4

activin

ActRIIA

Smad2/3 P P P

Targeting activin-A signalling in myeloma bone disease

Osteoblast blockade

Pre- osteoblast Smad4

+5T2MM Naïve +Veh +ActRIIA 0

5

10

15

20

25

30 p<0.001 p<0.001

Ob.

N (/

mm

)

Osteoblast No

+5T2MM Naïve +Veh +ActRIIA

0

10

20

30

40 p<0.001 p<0.001

Ob.

Pm (%

)

Osteoblast Perimeter

Naive

5T2MM+vehicle

5T2MM+ ActRIIA.mu.Fc

ActRIIA.mu.Fc prevents 5T2MM - induced decreases in osteoblast number

ActRIIA.mu.Fc prevents 5T2MM-induced bone loss and the development of lytic bone lesions in the tibia


2

4

6

8

10

14 p<0.001 p<0.001

BV/T

V (%

)

Trabecular Volume

12


10

20

30

40

50

60 p<0.05

Num

ber

Lesion Number p<0.05

Naive 5T2MM+Veh 5T2MM+ActRIIA

5T2MM+Veh 5T2MM+ActRIIANaive

0.0000

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

naïve 5T2MM + veh 5T2MM +ActRIIA

BFR

/BS

(mm

2 xm

m-3/m

m/d

ay)

B. i. mineralising surface – CE ii. bone formation rate – CE iii. mineral apposition rate – CE p<0.01 p<0.05

naive naive

*

NAIVE

0.0010.0020.0030.0040.0050.0060.0070.00


MS

(%

)

p<0.01 p<0.05

MS

(%)

BFR

(mm

2 xm

m3 /

day)

0.0000

0.2000

0.4000

0.6000

0.8000

1.0000


mic

rons

/day

p<0.01 p<0.05

mic

rons

/day

Naive 5T2MM 5T2MM + ActRIIa.muFC

Chantry et al; JBMR, Dec 2010

Inhibiting Activin-A Stimulates Bone Formation and Prevents Cancer induced Bone Destruction

Treatment with ActRIIA.mu.Fc reduces tumour burden in bone and increases survival

0 0.05 0.10 0.15 0.20 0.25 0.30 0.35

Para

prot

ein

(g/L

)

Naive + veh + ActRIIA 5T2MM


b

0

20

40

60

80

100

5T2M

M C

ells

(%)



a

0 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40

Sple

en w

eigh

t (m

g)



c d

50

100

0 10 20 30 40

Days

Surv

ival

(%)

5T33MM+veh

5T33MM + ActRIIA

p<0.05

Proteasome inhibitors also exhibit bone anabolic effects

• The addition of the highly effective proteasome inhibitor, bortezomib (‘Velcade’) as an anti-tumour agent in myeloma has become a mainstay of treatment worldwide (Harousseau et al, 2010; Dimopoulos et al 2009, Jagannath et al 2006)

• One fortunate consequence of proteasome inhibition is reduced degradation by the proteasome of β-catenin, a common mediator of the osteoblastogenic Wnt signalling pathway.

• Specifically, indices of bone remodelling appear to normalise in patients treated with bortezomib (Zangari et al 2005, Terpos et al 2006, Qiang et al 2009)

• Novel proteasome inhibitors, with improved side effect profiles, such as carfilzomib, are also achieving positive effects on bone remodelling via stimulation of the Wnt signalling pathway (Hurchla et al 2013, Hu et al 2013).

The effects of immunomodulatory drugs (IMiDs) such as thalidomide and lenalidomide on myeloma bone disease

• The effects on bone of IMiDs has been studied by several investigators with some conflicting evidence.

• Recent in vitro studies have demonstrated an inhibition of osteoblast activity as shown by reduced mineralisation and alkaline phosphatase activity (Bolomsky et al 2014).

• However, clinical studies have demonstrated positive effects on bone disease which may be independent of their anti tumour effect. Anderson et al 2006 have shown that thalidomide attenuates RANKL induced osteoclastic bone formation via downregulation of the transcriptional factor PU.1.

• Furthermore, treatment of patients with thalidomide and dexamethasone for relapsed and refractory myeloma led to normalization of the sRANKL/OPG axis in addition to substantial anti tumour activity (Terpos et al 2005).

• Similarly, lenalidomide has also been associated with reduced osteoclastic bone resorption due to inhibition of the osteoclast activating factors APRIL (a proliferation inducing ligand) and BAFF (B-cell activating factor)171 (Breitkreutz et al 2006).

Denosumab (Amgen) – myeloma data awaited, NICE due to deliberate

• Denosumab (Amgen) is a fully humanised monoclonal antibody against RANKL and has been in development over the last decade as an alternative to bisphosphonates as an anti-resorptive strategy in myeloma bone disease, other tumours that metastasize to bone (eg breast, prostate* myeloma data to follow) and in osteoporosis.

• A debate is thus raging between Amgen sponsored trials showing superiority, or at least non-

inferiority of denosumab and other Novartis (Zol) sponsored studies which suggest that denosumab is not cost effective.

• Administration of denosumab does have some attractive features including lack of renal toxicity and

monthly sub-cutaneous administration likely to facilitate easier, quicker and possibly domicilliary administration. Similar efficacy, similar ONJ rates, hypocalcaemia more common.

• Markers of bone resorption are suppressed for longer in patients on denosumab (Body et al 2006). • Denosumab more effective than iv bisphosphonates after previous treatment with iv

bisphosphonates (Smith et al, NEJM 2009) • Recent head to head study between denosumab and zolendronic acid in patients with myeloma or

advanced metastatic cancer (excluding breast and prostate cancer). Did not show superiority of denosumab in terms or increase non-inferiority was demonstrated ‘trending towards superiority’. Ease of subcutaneous administration and lack of renal toxicity were heralded as clinically important (Henry et al, JCO 2011).

Bruton tyrosine kinase (BTK) inhibition

• The BTK is a non-receptor tyrosine kinase expressed in maturing B-cells and implicated in B-cell maturation (Burger et al 2013). BTK is expressed in MM cells and also osteoclasts, at least those seen in murine models (Tai et al 2012).

• Blockade of BTK using BTK inhibitors such as ibrutinib have been shown to inhibit tumour growth via down regulation of NFκB, STAT3, ERK1/2 and AKT signalling (Edwards et al 2012).

• A direct inhibition of osteoclast activity has also been demonstrated in a SCID-hu murine model of myeloma (Tai et al 2012). This, in turn, is proposed to have an anti tumour effect via reduction of OC derived tumour growth factors.

• BTK inhibition is also proposed to prevent the adhesion of MM cells to bone marrow stromal cells (BMSCs) and to reduce the release of BMSC derived growth factors including IL-6, SDF-1, M-CSF and MIP1-α (Tai et al 2012).

Radionuclides used in the treatment of myeloma bone disease that stimulate bone formation

• A number of radionuclides, or radiopharmaceuticals have been trialled in

the treatment of myeloma and other cancers that metastasize to bone. They have an affinity for bone undergoing active remodelling and are able to deliver a localised radiotherapeutic effect.

• In the treatment of prostate cancer positive effects on the reduction of bone metastases and bone pain have been reported after treatment with Samarium EDTMP (Autio et al 2013). This agent has also been trialled in patients with myeloma and bone pain with substantial improvements in bone pain (Abruzzesse et al 2008).

• Strontium ranelate (Bolvin et al 2012) has also demonstrated safety and efficacy in the treatment of osteoporosis and has been shown to increase bone formation rate. This agent may prove effective as a treatment for myeloma induced bone disease although clinical data so far is limited.

Recombinant parathyroid hormone

• Similarly, treatment with recombinant parathyroid hormone (rPTH ‘teraparitide’) demonstrates reductions in vertebral and appendicular fractures in patients with osteoporosis(Hodsman et al 2005), as well as increased bone mineral density in animal models of myeloma (Pennisi et al 2010).

• The actions of rPTH are controversial since there is conflicting evidence that rPTH can also stimulate osteoclastogenesis (Lowik et al 1989).

• There have been isolated reports of malignancies occuring in patients on rPTH including a case report detailing the emergence of myeloma in a patient with osteoporosis treated with rPTH (Forslund et al 2008). Although these reports are exceptional, they have halted, for now at least, exploration of rPTH therapy in patients with MBD.

LOW HIGH

NORMALISED EXPRESSION

Bone anabolic target




Apoptotic target

Immuno-modulatory target

Cytotoxic target

Towards personalised

medicine

Conclusions

• In recent years, survival outcomes for patients with myeloma have substantially improved.

• However, the disease remains almost always incurable. • Many patients continue to suffer severe skeletal morbidity which, despite

current treatments, is associated with chronic pain, dependency on analgesia and substantially compromises quality of life.

• Skeletal complications also contribute to a shortened life expectancy. • Better treatments for MBD are needed, including more targeted inhibition

of osteoclastogenesis beyond the standard of care with BP. • Added benefit may come from the addition of bone anabolic agents such

as anti-Dkk-1, anti-TGFβ-1 and anti-HGF. • Improvement in survival may be achieved not only from the direct

benefits of maintaining and restoring skeletal health but also from additional anti-tumour effects associated with bone targeted therapies.

Myeloma bone disease: Managementnssg.oxford-haematology.org.uk/.../myeloma-bone... · Thames Valley Cancer Network – Update in Myeloma and Plasma Cell Dyscrasias • In May 1840,

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