Which bisphosphonate?

How long do you give it for?

What about Denosumab?

What is the most effective method of preventing bone disease in

patients with myeloma?

Which bisphosphonate?Meta-analysis and Cochrane review (20 randomised controlled trials incorporating 6692 patients) Mhaskar et al 2012

16 trials were bisphosphonate vs no bisphosphonateGreat heterogeneity between trials and various bisphosphonates used ie ibandronate, etridronate not used in myeloma

Reduced skeletal events, vertebral fractures and pain

Zoledronate appeared to be superior to etidronate, clodronate and placebo. No trial of zoledronate vs pamidronate

Phase III trial comparing denosumab to zoledronic acid in patients with at least 1 osteolytic lesion (Henry et al., 2011). Densumab is subcutaneous, has no need for renal monitoring, and without the burden of acute phase reactions

0 6 12 18 24 30 36 42 48 54 60 66 72

MRC Myeloma IX— ZOL ↓ SREs vs CLO Regardless of Baseline Bone Disease

Abbreviations: CLO, clodronate; SRE, skeletal-related event; ZOL, zoledronic acid. a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic bone lesions.

Bone disease at baseline No bone disease at baseline

0.5

0.4

0.3

0.2

0.1

0

Time from randomization, months

Cum

ulati

ve in

cide

nce

func

tion,

SREs

/pati

ent

668682

415402

325297

250212

189164

136117

10075

6950

5037

3524

1812

64

00

ZOLCLO

Patients, n

0 6 12 18 24 30 36 42 48 54 60 66 72

0.5

0.4

0.3

0.2

0.1

0

Time from randomization, monthsCu

mul

ative

inci

denc

e fu

nctio

n,SR

Es/p

atien

t

302276

241212

185159

135118

9291

6356

3837

2824

1818

1112

87

54

00

ZOLCLO

Patients, n

CLO

ZOL

CLO

ZOL

MRC Myeloma IX— ZOL Significantly OS vs CLO in Patients With Bone Disease at

Baseline (n = 1,350)

50

60

70

80

90

100

40

30Ove

rall

Surv

ival

, %

20

10

0

0 1 2 3 4 5 6

668682

544534

447437

292271

165143

6453

30

Time Since Initial Randomisation, years

Clodronate (n = 682)Zoledronic acid (n = 668)

P = .0107HR = 0.82 (95% CI, 0.70-0.96)

+ Censored

ZOLCLO

Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; OS, overall survival; ZOL, zoledronic acid.Morgan GJ, et al. Lancet. 2010;376(9757):1989-1999.

∆ ~10 mo

Median follow-up = 3.7 years

8

Zoledronate is the better than clodronate

Unclear if zoledronate is better than pamidronate but quicker to give

ONJ rate less than 5% probably BUT much less if good dental care immediately from diagnosis and awareness of ONJ. Stop zoledronate or pamidronate around dental procedures

Be aware of renal function and hypocalcaemia

Future researchDuration and frequency of zoledronateRate of skeletal events after 2 years in a patient with stable disease is very low (but MMIX)

Randomised trial needed: zoledronate monthly indefinitely vs reduced frequency or stopping after fixed time if stable disease

Data on using bone biomarkers to assess duration and frequency Randomised trial needed: zoledronate monthly indefinitely vs stopping or reducing based on bone biomarkers

Data on new bone agents vs bishophosphonatesOngoing tial of denosumab vs zoledronate. Other newer agents around

Role of imaging in Myeloma and MGUS in 2015

As a diagnostic tool (especially new definition by IMWG)

In evaluating spinal disease for management (conservative vs surgery, vertebro/kyphoplasty, radiotherapy)

In evaluating non-spinal disease for management (conservative, radiotherapy, surgery)

Baseline for monitoring especially non-secretory, oligo-secretory, plasmacytoma, extramedullary disease

Could identify potential complications

Prognostic information

Skeletal survey, whole body MRI, whole body low dose CT scan, FDG-PET

Skeletal survey (=£100). Standard of care for decades. Numerous plain radiographs Requires patient to move in various positions. Takes time. Lacks sensitivity compared to newer techniquesCannot distinguish cause of vertebral wedge fractures and osteopenia

Whole body MRI (=£200)Limited capacity and limited experience in most units. Takes time The best in terms of sensitivity –picks up infiltrative disease as well as focal disease. Presence of infiltrative disease – can be difficult to assess. Does not alter management currentlyPicks up extramedullary diseaseNo radiationSome patients not suitable (unbale to lie still, pacemaker, claustrophobia)Not very useful for follow up or assessment of responseNewer techniques = Diffusion weighted MRI (see Messiou and Kaiser, BJH 2015)

Whole body low dose CT scan (£150)?Probably more capacityWill pick up focal disease ?as good as MRI but not good for infiltrative diseasePicks up extramedullary diseaseSome radiationNot useful for follow up or assessment of response

FDG-PET in myeloma (£650)Less experience, still need to confirm if positive lesion an osteolytic lesion on the CT portion . Radiation, capacityBetter for monitoring especially non-secretory or oligosecretory disease or major extramedullary disease

For detection of focal disease IMWG has not specified which cross sectional imaging technique to use

Focal lesion >5mm so all techniques (?PET especially) may pick up equivocal activity

Skeletal survey, whole body MRI, whole body low dose CT scan, FDG-PET

Where is cross sectional imaging most likely to be most useful or Cost effective

Patients with suspected smouldering myeloma (because of new IMWG recommendations greater than one FOCAL lesion due to myeloma is an indication for treatment IMWG 2014)

Patients with symptomatic spinal disease where myeloma is a possible or known diagnosis

Patients with symptomatic non-spinal disease where cross sectional imaging may provide useful information for management (i.e. when plain radiography negative or ambiguous)

As mandatory work up for solitary plasmacytoma

For non-secretory or oligo-secretory disease or significant extrameduallry disease, PET is useful for monitoring

IN THESE CASES IT MAY BE COST EFFECTIVE TO NOT DO A SKELETAL SURVEY AND GO STRAIGHT TO CROSS SECTIONAL IMAGING

Where is cross sectional imaging most likely to be least useful or cost effective

LEAST USEFUL

For asymptomatic patients with suspected MGUS? NO. Capacity is an issue with MRI so not recommended to order cross-sectional imaging Assess risk of MGUS and avoid radiology if low risk and perhaps intermediate risk unless unexplained bony symptoms

More controversial:Newly diagnosed patients with little in the way of bony disease and no bony symptomsWhy – currently cross sectional imaging techniques have limited value in follow up so limited value at diagnosis?

Early relapse after autologous stem cell transplant20% of patients relapse within a year of first auto-SCT

Median overall survival for this group is around 20-26 months from diagnosis (Kumar et al; Jimenez-Zepeda et al 2015) and probably only a year after relapse

Various “risk” factors (few papers on this)Failure to achieve CR pre-transplantMore than one induction regimenHigh B2M

More likely to have high risk genetics - >1 high risk genetic abnormality/poor gene expression profile/plasma cell leukaemia

EARLY RELAPSE <12 MONTHS POST AUTO = “ULTRA” HIGH RISK DISEASE as outlook so poor (<1-2 years)

UNMET NEED

Patients will have already had exposure to at least one novel agent during induction most likely bortezomib

Conventional strategies unlikely to lead to survival >1 year

Therefore experimental approaches warranted (if patient wants) = clinical trials

Current concepts of treating high risk disease (based on little evidence) would suggest continuous therapy approach with a maintenance strategy

Combination of IMID + newer proteasome inhibitor+ antibody +/- steroid /cyclophosphamide

Daratumumab, Pomalidomide, Carfilzomib/Ixazomib, new agentsAllogeneic transplantation/immunotherapy

DARATUMUMAB anti CD38 monoclonal antibody

Single agents studies = 36% PFS 6 monthsRelapsed patientsDaratumumab + lenalidomide + dexamethasone. Early data = 75-100% response rate. Well tolerated

Newly diagnosedDaratumumab + bortezomib based regimensbortezomib-dexamethasone (VD), bortezomib- thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP)

Daratumumab + pomalidomide-dexamethasoneAll early days but very well tolerated, fast response, PBSCH successful

Isatuximab/SAR 650984, a Therapeutic Anti-CD38 Monoclonal Antibody (SANOFI)

A Phase Ib Dose Escalation Trial of SAR650984 (Anti-CD-38 mAb) in Combination with Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple MyelomaIn heavily treated patients 64.5% response rate and VGPR of 23% - note 74% refractory to lenalidomide, 48% prior carfilzomib

396 PATIENTS IN EACH ARM

PFS was significantly improved by 8.7 months with KRd (HR, 0.69; P<0.0001)

An unprecedented median PFS of 26.3 months with KRd

Interim OS analysis: trend in OS favouring the KRd group; Kaplan-Meier 24-month OS rates 73.3% (KRd) versus 65.0% (Rd)

ORR was higher with KRd (87.1% vs 66.7%); significantly more patients achieved ≥CR (31.8% vs 9.3%)

ASPIRE TRIAL

Allogeneic stem cell transplantation

Controversial high TRM of 10-20% with reduced intensity conditioning. Timing important as less effective and higher toxicity with later relapses –i.e not so good in this setting

Need for graft versus myeloma effect but this is linked with GVHD. Disappointing PFS at 5 years ?around 20%

Conflicting data in various studies versus tandem auto studies

However some patients do get long term disease control“Selected” patients who understand risk of procedure