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Why should the physician be interested in Multiple Myeloma and Related Disorders?

Graham Jackson

Malignant Plasma Cells in Marrow

How might a paraproteinaemia present to the general physician?

• AKI• VTE• NEPHROTIC SYNDROME • HEART FAILURE• HYPERCALCAEMIA• ANGINA • ANAEMIA• SPINAL CORD COMPRESSION• CVA/NSTEMI/RETINAL HAEMORRHAGE • NERVE ROOT COMPRESSION• INFECTION • RAISED TOTAL PROTEIN • MACROGLOSSIA

Plasma cell disorders

• Multiple Myeloma • MGUS• Amyloidosis • Plasmacytomas• Poems syndrome • Cryoglobulinaemias

Plasma cell disorders

• Multiple Myeloma

Multiple myeloma: Key facts

Multiple myeloma (MM) is a malignant plasma cell disease1

5,500 new cases of MM annually2 2,900 deaths by MM

annually2

2% of all new cancer cases2 71 median age of a

person affected3

33% 10-year survival rate, improved from 5% in the 1970s2

1. Palumbo and Anderson. N Engl J Med. 2011;364:1046–1060; 2. Cancer Research UK. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/myeloma. Accessed 8 March 2017; 3. Presentation by Eric Low, Myeloma UK. 4.. http://www.cancerresearchuk.org/about-cancer/myeloma/risks-causes. Accessed 8 March 2017

Survival is improving but multiple myeloma is still incurable

Cancer Research UK http://www.cancerresearchuk.org/cancer-info/cancerstats/types/myeloma/survival/ March 2015

Myeloma (C90): 1971-2011Age-Standardised Five-Year Net Survival, England and Wales

47%

11%

NET

5-Y

EAR

SURV

IVAL

(%)

Multiple MyelomaEpidemiology

Aetiology

• Causes remain uncertain

– Radiation, agriculture (farming), metals, rubber, chemicals, combustion fuel products.

– Familial and genetic factors have been implicated– Twice as common in patients of Afro-Caribean descent– All have pre-existing MGUS

Multiple MyelomaKey facts

• Myeloma is the cancer with most rapidly improving prognosis of all major cancer types

• Patients with Myeloma have to wait the longest between the first visit to GP with symptoms and diagnosis in the UK

• Of all cancers myeloma is most likely to be diagnosed in A and E or by the acute physician

Multiple Myeloma• Multiple myeloma is a cancer of bone marrow plasma cells

• It is characterised by

– monoclonal protein in serum and / or urine

– lytic bone lesions

– excess plasma cells in the bone marrow

What problems does myeloma cause?

Signs & Symptoms in 1027 Newly Diagnosed Myeloma Patients

0

10

20

30

40

50

60

70

80

Bonelesions

Fatigue Cr >2mg/dL

Ca >11mg/dL

Wt loss(>9 kg)

% p

atie

nts

79

Hb<12g/dL

73

Bonepain

66

32

1319

12

Kyle RA. Mayo Clin Proc 2003;78:21-33

What problems does myeloma cause?

• Renal failure

Almost 50% of patients with MM have a low eGFR at presentation (2005-present; 650 consecutive patients )Dimopoulos: Annals of Oncology 25: 195–200, 2014

Why do patients with myeloma getrenal damage?

• Light chain toxicity

Cortex

Outer medulla

Inner medulla

Cast injury

Glomerulus

Light chains filtered

Distal tubule

10-30g/day absorption

Toxic injury

5-10mg/day in urine

Thick ascending limb Light chains + Tamm-Horsfall proteins produce casts

“Fractured cast”

Renal biopsy appearances in cast nephropathy

Why do patients with myeloma getrenal damage?

• Light chain toxicity• Hypercalcaemia• Dehydration• Nephrotoxic drugs – particularly NSAIDS• Infection• Hyperuricaemia

Why do patients with myeloma getrenal damage?

• Light chain toxicity –treat disease ASAP with novel therapies

• Hypercalcaemia – hydration, bisphosphonate• Dehydration - hydration• Nephrotoxic drugs – stop• Infection - treat• Hyperuricaemia – hydration, allopurinol

eGFR normalises in the majority of patients with MM and renal impairment

eGFR

Risk of death after diagnosis in England of MM by year in patients who received in-hospital dialysis (P<0.001)

Evison et al. Br J Haematol. 2016.

What problems does myeloma cause?

• Renal failure• Amyloid

Presenting Features

Renal:• Nephrotic Syndrome• Chronic kidney disease• Drug intolerance• Dialysis

Other:• Carpal Tunnel Syndrome• Painful arthropathy• Fatigue• Lymphadenopathy• Bruising/purpura

GI:• Malabsorption• Weight loss• Hepatosplenomegaly• Mallory Weiss tears

Cardiovascular:• Cardiomyopathy• Heart failure / LVD• Arrythmias• Sudden death

Soft Tissues:• Macroglossia• Periorbital purpura

Autonomic/sensory Neuropathies• Postural Hypotension• Paraesthesia + weakness• Hypo/hyperhydrosis• Bladder and bowel dysfunction

Consider amyloidosis if...• Unexplained Cardiomyopathy• Unexplained Nephrotic Syndrome• Sensorimotor/Autonomic Neuropathy• Macroglossia

• Typically aged 50-70 years

1. Google Images: http://images.google.co.uk/imghp?hl=en-GB&ie=UTF-8&tab=wi3. BJH Guideline: Guidance on the diagnosis and management of AL amyloidosis

• No blood test can be used to diagnose amyloidosis• Biopsy Rectum, gums, abdominal fat

• Congo Red StainApple green birefringance

• Biopsy!

If you suspect amyloid...

What problems does myeloma cause?

• Renal failure• Amyloid• Hypercalcaemia• Bone problems

Multiple ‘punched-out’ lytic lesions in the skull in myeloma

Wedgecompressionfracture of athoracicvertebra

• FDG avid tumour1

• Visualisation of lytic component to lesions on CT1

• Assess disease response

PET-CT

Bisphosphonates

Treatment of Bone Disease

• Hypercalcaemia

– IV fluids

– Steroids

– Bisphosphonates – with care!!

Cochrane Review

• 11 trials, 2183 patients

• Prevent vertebral fractures OR 0.59 (0.45-0.78) p <0.00005• Amelioration of pain OR 0.59 (0.46-0.76) p <0.00005

MRC Myeloma IX

43SREs 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.Abbreviations: CLO, clodronate; SRE, skeletal-related event; ZOL, zoledronic acid.

Highlights the importance early diagnosis and of treating all patients regardless of skeletal morbidity at presentation

0 6 12 18 24 30 36 42

Bone Lesions at Baseline No Lesions at Baseline

0.5

0.4

0.3

0.2

0.1

0

Time From Randomisation, months

Cum

ulat

ive

Inci

denc

e Fu

nctio

n,SR

Es/p

atie

nt

668682

415402

325297

250212

189164

136117

10075

6950

ZOLCLO

Patients, n

0 6 12 18 24 30 36 42

0.5

0.4

0.3

0.2

0.1

0

Time From Randomisation, months

Cum

ulat

ive

Inci

denc

e Fu

nctio

n,SR

Es/p

atie

nt

302276

241212

185159

135118

9291

6356

3837

2824

ZOLCLO

Patients, n

CLO

ZOLCLO

ZOLP = .004

43%

34%17%

9%

P = .007

Zometa overview

• Overall survival 45.5mo clodronate v 51.6 mo for zometa

• Overall survival advantage for Zometa v clodronate = 6 months mainly seen in BD pts

What problems does myeloma cause?

• Renal failure• Amyloidosis• Hypercalcaemia• Bone problems • Anaemia• Infection• Thrombosis

Myeloma Can Result in a Broad Spectrum of Clinical Manifestations

Hoffman R. Hematology: basic principles and practice, 5th edition; 2008. Ropper AH, et al. N Engl J Med. 1998;338:1601-1607.

M-protein

Bone pain

Neuropathy (33%)Hyperviscosity

Amyloidosis

Hypercalcemia (15% to 20%)

Immunedeficiency

Anemia (10% to 35%)

Lytic lesions (70%)

Infection (15%)

Marrow infiltration

Multiple myeloma cells

Destruction of bone

Renal compromise (30%)

MGUS

Monoclonal Gammopathy of Undetermined Significance

• Bone marrow plasma cells <10%

• Paraprotein less than 30g

• No CRAB (hyperCalcaemia, Renal impairment, Anaemia and Bone disease)

Prevalence of MGUS

MGUS

All myeloma patients have a pre-existing MGUSOver 20 years • 25% will progress to myeloma

– RISK FACTORS

• IgA paraprotein• PP > 15g• Abnormal SFLC

Risk stratification system for MGUS Rajkumar, V et al (2005) Blood 106: 812-7

Risk group No of patients Relative Risk Abs risk @ 20y 20y death-adjusted risk

Low risk:M-band <15g/LIgG isotypeSFLC ratio 0.26-1.65

449 1 5% 2%

Low-intermediate: any 1 factor

420 5.4 21% 10%

High-intermediate: any 2 factors

226 10.1 37% 18%

High risk: all 3 factors

53 20.8 58% 27%

Asymptomatic Myeloma

Asymptomatic/smouldering myeloma

• Higher risk of progression than MGUS:– 50% at 5 years– 65% at 10 years

• Cumulative probability: 70% at 15 years• Median time to progression: ≈5 years

Kyle R. N Engl J Med 2007; 356:2582-90

10%

3%1%

Smouldering Multiple Myeloma (SMM): Risk of progression to active disease

Symptomatic Myeloma

Myeloma Prognostic Factors

• Serum β2 microglobulin• Cytogenetics • Albumen • Age• LDH • Peripheral blood plasma cells

The International Staging System (ISS)Prognostic model based on β2-microglobulin and albumin

Patients < 65 y

Patients > 65 y

Stage Criteria

Iβ2m < 3.5 mg/L

& albumin ≥ 3.5 g/dL

II Not stage I or III

III β2m ≥ 5.5 mg/L

Greipp et al. J Clin Oncol 2005;23:3412-20

Standard risk factors and the revised ISS

Palumbo et al. J Clin Oncol 2015;33(26):2863-9

Overall survival according to R-ISS stratification

Palumbo et al. J Clin Oncol 2015;33(26):2863-9

Improving outcomes

1960-65

1965-70

1970-75

1975-80

1980-85

1985-90

1990-95

1995-00

2000-05

2005-10

Early deaths in high risk

No plateau

Adapted from Kumar SK, et al. Leukemia. 2014;28:1122-1128.

Despite Improving Survival With New Drugs 1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20

Follow-up From Diagnosis (Yrs)

Prop

ortio

n Su

rviv

ing

Outcomes by decade

Impact of UK Myeloma Trials

Why are things changing?

Ocio, Leukemia 2014. Updated

The agents we have available

Raf

MEK

MAPK

PI3K

Akt

Ras

mTORC1 mTORC2

Lymph.NK cell

Approved

ThalidomideLenalidomidePomalidomide

IMiDs

PanobinostatVorinostatRomidepsinGivinostatRocilinostat

DACi

CS-1 ElotuzumabCD38 Daratumumab / IsatuximabCD138 nBT062-DM4CD56 LorvotuzumabCD40 Dacetuzumab / LucatumumabBAFF TabalumabKiR IPH2101PD1/PDL1 Pembrolizumab / Nivolumab / Pidilumab

IL-6 Siltuximab

mAb

BortezomibCarfilzomibIxazomibOprozomibMarizomib

Proteasome Inh.

MelphalanCyclophosphamideBendamustineMelflufenTH-302

Alkylators

TanespimycinAUY922

Hsp-90 Inh.

DNA Damaging ZalypsisPARP Inhibitor Veliparib

Other DNA damaging

KSP Inh FilanesibAurora K Inh MLN8237CDK 4/6 Inh Seliciclib

Cell cycle Inh.

AKT Perifosine / AfuresertibmTORC1 Everolimus / TemsirolimusmTOR C1/C2 MLN0128 / INK128Farn Transf Tipifarnibp38/MAPK inh SCIO-469p38/JNK act AplidinMEK SelumetinibBcl-2 VenetoclaxXPO SelinexorPIM PIM447

Signaling Pathways

CDK 1, 2, 5, 9 Dinaciclib / TG02FGFR3 Dovitinib / AB1010 / MFGR 1877ScKit /PDGFR Imatinib / DasatinibVEGF-R BevacizumabIGF-1R AVE1642 / CP-751, 851EGF-R CetuximabPKC EnzastaurinBTK IbrutinibKinase Inhibitors

Thalidomide

Event-free survival Overall survival

Palumbo et al. Lancet 2006

MPT vs MP in elderly patients with MM –Survival

Event-free survival Overall survival

Palumbo et al. Lancet 2006

MPT vs MP in elderly patients with MM –Survival

Velcade

Phase III VISTA trial: VMP vs MP

0 3 6 9 12Time (months)

15 18 21 24 270

20

40

60

80

100

VMP

Patie

nts

with

out e

vent

(%)

Time (months)0 4 8 12 16 20 24 28 32 36 40

0

20

40

60

80

100

Patie

nts

with

out e

vent

(%)

Time to progression Overall survival

San Miguel et al. N Engl J Med 2008;359:906–917San Miguel et al. ASH 2008 (Abstract 650); oral presentation

ORR: VMP 71%, MP 35%, CR: VMP 30%, MP 4%

Median follow-up 25.9 mos3-year OS:

VMP: 72%MP: 59%P=0.0032

VMP: 24.0 mosMP: 16.6 mosP<0.000001

MP

VMP

MP

ORR, overall response rate.

Monoclonal antibodies

POLLUX: standard therapy +/- Daratumumab

Usmani SZ, et al. Presented at ASH 2016 (Abstract 1151), oral presentation.

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 18 21 27

283286

249266

206249

181237

159227

132194

515

01

RdDRd

No. at risk Months24

00

15

4882

76%

49%

18-month PFS*

Rd

DRd

Median: 17.5 months

HR: 0.37 (95% CI, 0.28-0.50; P <0.0001)

Ove

rall

resp

onse

rate

, %

15

32

32

25

2312

23

8

0

10

20

30

40

50

60

70

80

90

100

DRd (n = 281) Rd (n = 276)

sCR

CR

VGPR

PR

ORR = 93%

ORR = 76%

P <0.0001

≥VGPR: 78%a

≥CR: 46%a

≥VGPR: 45%

≥CR: 20%

Median: not reached

Note: PFS: ITT population; ORR: response-evaluable population.*Kaplan-Meier estimate; aP <0.0001 for DRd vs Rd.

Median follow-up: 17.3 (range, 0-24.5) months

DRd-treated patients had a 63% reduction in the risk of disease progression or death in comparison with Rd Responses continue to deepen in the DRd group with longer follow-up

Age and frailty

Prob

abilit

y of

sur

viva

l (%

)

Age < 75 yearsAge ≥ 75 years

0.00

0.25

0.50

0.75

1.00

0 0.5 1 1.5 2 2.5 3

Time since diagnosis

Negative impact of age on survivalMeta-analysis of European trials (MP vs MPT, VMP vs VTP, VMP vs

VMPT-VT); 1435 newly diagnosed MM patients

3-year OS

< 75 years 68%

≥ 75 years 57%

2013;98(6):980-987

Frailty score predicts outcome

PFS OS

Prog

ress

ion-

free

Surv

ival

0.00

0.25

0.50

0.75

1.00

0 12 18 24 30 36Months

FitIntermediate FitnessFrail

6

Ove

rall

Surv

ival

0.25

0.50

0.75

1.00

FitIntermediate FitnessFrail

0.000 12 18 24 30 36

Months6

Palumbo A, et al. Blood 2015, 125: 2068-74

Frailty score predicts non-hematological toxicity and discontinuation rate

Discontinuation rate

Cum

. Inc

. Non

-hae

mat

olog

ical

AEs

0.00

0.25

0.50

0.75

1.00

0 12 18 24Months

FitIntermediate FitnessFrail

6 Cum

ulat

ive

Inci

denc

e D

isco

ntin

uatio

n

0.25

0.50

0.75

1.00 FitIntermediate FitnessFrail

0.000 12 18 24

Months6

Palumbo A, et al. Blood 2015, 125: 2068-74

Non-hematological toxicity

Conclusions• Plasma cell disorders are very relevant to the physician.

– VTE– Renal failure/AKI/nephrotic syndrome– Bone pain/SCC– Hypercalcaemia– Cardiomyopathy– Neuropathy – Infection/sepsis– Unexplained anaemia/raised ESR– Raised TP

Conclusions

• Plasma cell disorders are very relevant to the physician. • Myeloma can cause devastating problems that are largely

avoidable or reversible with prompt diagnosis.• The prognosis for all plasma cell disorders is improving rapidly

with multiple new therapies