Myeloma for Diagnosticians

Dr Mamta Garg

Consultant Haematologist

What is Myeloma?

Malignant disorder of plasma cells

• an excess of abnormal plasma cells >10%

• paraprotein in the serum and/or urine

• End organ affection CRAB, SLiM CRAB

Diagnosis: Paraprotein or M protein SPEP

CRAB and now “Slim CRAB”

• Myeloma defining events or Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

– C: Hypercalcaemia: serum calcium >0·25 mmol/L higher than the upper limit of normal or >2·75 mmol/L R: Renal insufficiency

– R: Creatinine clearance <40 mL per min or serum creatinine >177 μmol/L (>2 mg/dL)

– A: Anaemia: Hb >20 g/L below usual Hb, or a Hb <100 g/L

– B: Bone lesions: one or more osteolytic lesions on XR, CT or PET-CT

• Any one or more of the following biomarkers of malignancy:

– S (M-spike): Clonal bone marrow plasma cell percentage* ≥60%

– Li: Involved:uninvolved serum free light chain ratio≥100 (or <0.01)

– M: >1 focal lesions on MRI studies of 1 cm in size

Rajkumar et al. Lancet Oncol. 2014 Nov;15(12):e538-48

Asymptomatic/Smouldering Myeloma

• M protein present in serum and/or urine

• Plasma cells >10% in the marrow

• No CRABs

• It carries a higher risk of progression to frank

multiple myeloma (10% per year the first 5

years) compared with MGUS

ISS, now Revised ISS or R-ISSLDH and FISH analysis on BM sample mandatory

ISS STAGE CRITERIA

I B2M <3.5 Albumin >35

II B2M >3.5 but <5.5 or Albumin

<35

III B2M >5.5

RISK CRITERIA

Standard No high risk chromosomal

abnormalities (CA)

High Risk T(4:14), t(14:16) del 17p Iq

gains, Ip loss and t(16:20)

RISK CRITERIA

Normal Normal Serum LDH <upper

limit of normal

High High serum LDH >255 for us

R-ISS STAGE CRITERIA

I ISS I and standard risk

cytogenetic abnormality and

normal LDH

II Not R-ISS I or III

III ISS stage III and either high risk

CA by iFISH or high LDH

IMWG report Palumbo et al JCO Aug 3 2015 61 2267 Munshi et al IMWG panel 2 consensus recommendations

for risk stratification Blood 2011 117 4696-4700

R-ISS risk stratify and helps to prognosticate

ISS CA High

LDH

R-ISS PFS m OS m Non Tx Tx

based

iMiD PI

I No No I 66 NR 66 NR NR NR

I Y/N Y/N II 42 83

(8 yrs)

70 88 88 81

II II 42 83 70 88 88 81

III y/N Y/N III 29 43

(3.5 y)

41 42 40 47

IMWG report Palumbo et al JCO Aug 3 2015 61 2267 Munshi et al IMWG panel 2 consensus recommendations

for risk stratification Blood 2011 117 4696-4700

NCIN. Haematological malignancies in England 2001-2008

Age-specific incidence rates by age group for myeloma in males and femalesbetween 2006-2008 in England

Demographics

• Myeloma is a disease of the elderly

• In UK median age at diagnosis 73 years

• Latest USA registry data: 55% are ≥ age 75 (1975-2010)

• More and more patients >87 years

• Incidence: 65-70 new symptomatic cases per year in Leicester (68/million)

• Additional 10 Asymptomatic myeloma per year

Changing demographics

• Incidence and prevalence of myeloma expected to rise– Aging population predicted increased incidence of 57% between 2010-2030

– Better GP and medical education, high index of suspicion leads to earlier diagnosis

– Improved survival with novel therapies from 3.5 years to 10 years• therefore increased prevalence

– Disease biology is different in very elderly myeloma – sometimes responds to dexamethsone alone giving patients survival of >12m – it is difficult to tell clinicians not to test/diagnose over 90

– Treated up to 97 years of age with steroids alone above 90 years age

Natural course of disease

1st line

treatment

2nd line

treatment

3rd line

treatment

MGUS: Monoclonal gammopathy of

undetermined significance

Survival improving

Shahjikumar Leukemia(2017) 1915–1921

Presentation

• De novo or following MGUS - <5%

• Bone problems– Back pain

– Spinal cord compression

– Pathological fracture

• Renal Failure

• Recurrent infections

• Anaemia….often macrocytic

• Chance finding…............ACR:PCR discrepancy on diabetic review

Who diagnoses/suspect Myeloma in

Leicestershire

• 90 consecutive NDMM patients assessed – symptomatic

• 33 from GP – 20 backache

– 17 anaemia

– 3 high ca

– 4 AKI

– 2 urine PCR and ACR discrepancy

• 34 from medics: a/w high ca, full house, AKI, anaemia, sepsis, radiology flag, skeletal lesions

• 12 Renal team with AKI and Igs is part of workup

• 5 radiology flag

• 3 spinal surgeon/orthopaedics

• 3 from MGUS or AMM monitoring – raises concern over monitoring practices

Presentation

• Back pain is the 2nd most common complaint in primary care

• <1% of patients presenting with back pain will have a malignant cause

• Back pain is the most common complaint in myeloma presentation (58%)

• Anaemia and any other abnormal blood parameter with back pain was highly predictive of ‘high risk’ back pain

• Average 11 months Time to diagnose from various pointers in blood test

J Am Board Fam Med November-December 2016 vol. 29 no. 6 702-709

Immunoglobulin molecule

Light chains are small molecules

Kappa ~ 25kDa

Lambda ~ 50 kDa

Can pass through GBM,

reabsorbed and metabolised in

proximal convoluted tubules

Capacity up to 500 mg/day

In Myeloma if the light chains are

produced in excess then the

capacity to be reabsorbed in PCT

is overcome and Light chains

appear in urine (Bence Jones

Proteinuria)

Urine protein and albumin

• Normally there should be no protein in the urine.

• Particles with a molecular mass of >60kDa cannot filter through the glomerular basement membrane (GBM)

• Albumin is 66.5 kDa cannot filter through glomerulus unless there is a structural damage to the glomeruli for ex in diabetic nephropathy

• Commonly found proteins in the urine are • Albumin in disease state in glomerular diseases

• free light chains in myeloma/MGUS (also called urinary bence jones UBJ)

• haemoglobin or myoglobin in specific disease states

• B2 Microglobulin

• Normal tubular protein like tams-horsfall protein <0.15 g/d

• Total urinary protein excretion in the normal adult < 150mg/day

• Total Albumin excretion should be < 30mg/day.

• http://bestpractice.bmj.com/best-practice/monograph/875.html

Urine PCR and ACR – usual report

• Normal Levels

• Urine PCR 0-30 mg/mmol

• Urine ACR 0-2.5 mg/mmol creatinine

• Urine Protein < 0.15 g/L

• Urine Albumin 0-15 mg/L

• PCR is raised in both BJ proteinuria as well as Albuminuria

• ACR is only raised in albuminuria

• Normally they are concordant as commonest disease state is albuminuria like in diabetes

• When discordant then alarm bells should be ringing for myeloma

• Like ..

Case History to illustrate

09/06/14 30/09/13 21/08/12

Urine PCR (0-30) 1312 1317 476

Urine ACR (0-2.5) 16.3 10.7

Urine Protein (<0.15) 5.51 g/L 6.32 g/L 3.62 g/L

Urine albumin (0-15) 78 mg/L 81 mg/L

Hb (115-160) 89 g/L Not done Not done

Serum Creatinine (60-120) 403 mmol/L 58 77

SB, 71 years female, presented with free light chain myeloma in June 2014

Free lambda on SPEP electrophoresis was 9.1 g/L (normal no band)

Free lambda on serum freelite assay was 23,660 mg/L (normal range 5.7-

26.3)

Her Urine PCR and ACR and serum creatinine in the preceding 2 years were

as follows:

Local data collection and analysis

100 consecutive patients with newly diagnosed

myeloma who presented from July 2014 to July

2016

• Urine PCR and ACR,

• Urine BJ positivity,

• serum freelite levels

• Presence or absence of renal impairment at

diagnosis

Results

• Urine BJ negative in 29 patients – 100% had serum freelite <250 mg/L denoting reduced or negligible renal risk

– 83% had normal Urine ACR and PCR and serum creatinine

– 17% had abnormal creatnine due to unrelated causes and not due to myeloma

• Urine BJ was positive in 66 patients – Urine PCR was done in 48 patients

– Normal PCR in 12 patients denoted negligible urine light chains or bence jones s/o low renal risk due to myeloma

– Urine PCR was abnormal i.e. >30 mg/mmol in 36 patients.

– PCR was x10 ACR in 27 patients (27 patients) who also had relatively higher serum freelite value >1000mg/L and were at maximum renal risk.

• In 14 patients urine ACR and PCR were available from before, Urine PCR was >30 and 2 x ACR value several months prior to diagnosis.

• PCR was 10 x ACR in 8 of these patients suggested that myeloma could have been diagnosed many months earlier as shown in examples above.

Follow up action after the study/audit

• Biochemistry department will insert a comment “If PCR is raised i.e. >30 mg/mmol and > twice the value of ACR, please send a urine sample to immunology for Bence Jones (light chains) proteinuria”

• GP newsletter was sent out in September 2016 emphasise the need to interpret the results of Urine PCR and ACR correctly and to request screening tests for myeloma i.e. urine Bence Jones protein early.

• Earlier diagnosis of myeloma will eventually result in reduced rates of complications, reduced morbidity and improved overall survival

• GP are understanding results of Urine ACR and PCR better and are asking for Urine BJ earlier.

Other unusual ways of diagnosing

myeloma

• Panhypogammaglobulinaemia

• Macrocytic anaemia – unexplained

• Hyponatraemia (pseudo)

• Hyperphosphatemia (pseudo)

• High total protein but low albumin

• Changes in Immunology lab – if a pp is detected automatically do serum freelites since Jan 2017

• Not to miss 15% of light chain myelomas

CM 55 years old male

• Na 131, Creat 140,

• Ca 2.49 PO4 2.70 (0.8-1.5)

• alb 26 glb x

• Hb 83

• Lymph 4.33, we missed plasmacytoid eclls in circulation in the lab

• 3 weeks later GP asked for Igs as he suspected myeloma

• IgG 90.2 IgA <0.25 IgM <0.15

• PP 69.6

Assessment of a patient - NG35

• Bloods: UE, LFT, Bone, CRP, FBC,

• Immunoglobulins/SPE and Serum Free Lite chain analysis

• B2M, LDH, Urate

• Urine Bence Jones Protein

• Urine ACR:PCR

• Bony involvement– Whole body MRI or PET-CT

– MR spine and pelvis

– Role of the Skeletal survey (40% Bone loss needed to make a lytic lesion)

• Bone marrow-with cytogenetics/FISH analysis (soon NGS for high risk signatures)

Imaging

Prognostic assessment: R-ISS

• B2M and albumin

• LDH

• Cytogenetics– t(4;14) IGH/FGFR3 4p16 (10-20%)

– t(14;16) IGH/MAF 16q23 (5-10%)

– t(14;20) IGH/MAFB 20q11 (2-5%)

– TP53 deletion 17p13 (10%)

– Chromosome 1 abnormalities

• Response to treatment

Treatment

• Aim of treatment

• At what stage to treat?

• Treatment types – intensive and non intensive

• Decision on treatment intensity

• Adjuvant Treatment

• Symptomatic treatment

• Radiotherapy

• Vertebroplasty and kyphoplasty

Aim of Treatment

• Not curative……..yet

• ‘Disease modification’

• Quality of life

• Allow patients to live as actively as possible until death

• Starting to redefine the goals of therapy towards at least deep and durable responses (and perhaps eventually a cure?)

On the road to cure?

Aim of treatment: QoL

• QoL is worse when disease activity is high

• QoL improves as the disease comes under control– Physical aspects of QoL especially pain and fatigue

• QoL improves with depth of response

Aim of treatment: Avoiding toxicity

• Elderly patients want QoL rather than survival

• Dose reduce if anticipated issues or toxicity

But

• 1st remission is usually the longest

• In the elderly there may only be one chance

• Toxicity assessment after each cycle

At what stage to treat?

� Only Symptomatic patients (CRABs)

� Take into account SLiM CRAB

� Weird and wonderful unusual presentation with neuropathies, cryoglb, cardiac or systemic amyloidosis, POEMS syndrome etc.

� At relapse i.e. rise of paraproteinpp by 5 g/L or 100 mg/L with some kind of symptoms

� Entity like Gradual serological relapse over years – and we do nothing is stable otherwise.

Treatment

• MDT approach

– Radiology

– Clinical oncology

– Spinal surgeons

– Interventional radiologists

– Renal team

• Offer all patients clinical trials where possible

• HOPE trials clinic

• Designated trials team CRA and CRN for blue team

• 29 clinical trials as PI so far.

Top 4/5 recruiter in the country/world for several trials

Evolution of Myeloma therapy

Adapted from: Kyle and Rajkumar. Blood 2008; 111(6): 2962-2972

1840 1850 1860 1870 1880 1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2012

1983

1975

Autologous transplantation

Durie-Salmon staging system

2005

2005

Cytogenetic classification

International staging system1956

Light chain types (later

termed kappa and lambda) recognized

1895

1928

First large case series of myeloma

Description of plasma cells

1844

1845Abnormal urine protein,

later termed Bence Jones protein

First documented

case

1845

1844

Steel and quinine

Rhubarb and orange peel

1962

1958

Melphalan

Corticosteroides

1999

Thalidomide

2002

2002

Bortezomib

Lenalidomide

HSP-90 inhibitors

HDACiPomalidomide

CarfilzomibElotuzumab

20152004

Bortezomib

2007

Lenalidomide

2013

Pomalidomide

2016

Ixazomib

Daratumumab

IMiD

PI

mAb

HDACi ElotuzumabPanobinostat

Carfilzomib

Six drugs licensed by EMA for treatment of

MM in last 4 years

EMA – European Medicines Agency

Technology appraisals and Cancer drug fund

Year TA number Drug Whom to give Stage of MM

2007 129 Velcade All MM 2nd line

2009 171 Len All 3rd line

2011 228 Velcade or

Thalidomide

Elderly 1st line

2014 311 Velcade and

thalidomide

Younf 1st line

2016 380 Panobinistat All 4th Line

Jan 2017 427 Pomalidomide all 4th line

July 2017 457 Carfilzomib No previous vel 2nd line

Dec 2017 CDF Ixazomib Restriction++ 3rd or 4th line

Jan 2018 CDF Daratumumab Restriction++ 4th line

March 2018 NICE TA Len elderly 1st line

Use combinations of Drugs

Proteasome inhibitorsBortezomib Subcut

Carfilzomib IV

Ixazomib Oral

ChemotherapyMelphalan

Cyclophosphamide

Adriamycin

Monoclonal antibodies

Anti CD 38 Daratumumab

Isatuximab

Anti SLAMF7 319 - Elotuzumab

SteroidPrednisolone

Dexamethasone

iMiDs

immunomodulators

Thalidomide

Lenalidomide

PomalidomideHDAC inhibitors

Vorinostat

PanobinostatBcl 2 inhibitor

Venetoclax

XPO inhibitor

Selinexor

Stem cell Transplant

Autologous or allogeneic

Treatment: Newer combinations

• Advantages– Less cytopenias, no central lines, often oral, outpatient

based, less nausea and vomiting, less neutropenic sepsis

• Disadvantages– Other side effects….....constipation, diarrhoea, peripheral

neuropathy, autonomic neuropathy, thrombosis, infection.......

– Cost

• Lengthier treatments…..maintenance

Factors in selecting relapse therapy

GI: Gastrointestinal; SPM: Secondary primary malignancies.Adapted from Ludwig H et al. Leukemia 2014;28:981–992

• Age

• Performance status

• Renal insufficiency

• Poor marrow reserve

• Neuropathy

• Other comorbidities

– Cardiac

– Diabetes

• Genetic background

• Biology of relapse

– Rate of rise

– Organ damage

– Extra-medullary

• Previous therapy

– Response depth and duration

• Mode of administration

• Doublet or triplet

• Sequencing vs combination

• Previous treatment

• Cost

• Toxicity

Myelosuppression

Neuropathy

Thrombosis

GI, cardiac

• Risk of SPM

PATIENT DISEASE TREATMENT

Decision on treatment and intensity

• Performance status

• Frailty assessment frailty score draft 2.docx

• What is available (NICE)

Fit

• Generally <75 years

• Induction (Velcade/Thalidomide/steroids)

• Autologous transplant

• (Maintenance if we could…..)

Unfit

• Generally >75 years

• Induction Velcade/melphalan/steroids

• Maintenance Velcade/dexamethazone

Frail

• Generally >86 years

• VMP superlite or Dexamethasone or

supportive care

• …...96 year old keen for treatment

• QOL always at forefront

Intensive arm

From 2014 to Jan 2018 to Jan 2019

MYELOMA First Line Second

Line

Third

Line

Fourth

Line

Fifth

Line and

more

Intensive

In 2014

CTD, VCD

1st transplant

May be velcade again

Dex, CTD

2nd transplant

Len Dex

alone

Bendamutine

with Thal

Intensive

CDF/NICE

In 2018

VTD/

VCD

CTD/VTD/VCD 2nd

ABMT

Dex alone

Kd (velcade naïve)

Ixazomib

with len dex

Darzalex PVD(T) #16

Pom Dex

Benda Thal

Intensive

in June 2018

VRD-R Still none appropriate

Dara Vel Dex may come

by 2019

Kd stays

Ixa Len Dex

defunct

Darzalex

defunct

PVD(T) #16

Pom Dex

Benda Thal

Available trials

today

MUK9a and b IKEMA

BOSTON

Myeloma XII

IKEMA

BOSTON

IKEMA

BOSTON

COLUMBA

MUK8

Trials in Jan

2019

Myeloma XV MUK12 MUK12 MUK12

Non intensive arm from 2014 to 2019

MYELOMA First Line Second

Line

Third

Line

Fourth

Line

Fifth

Line and

more

In 2014 CTDa Vel Dex Len Dex

In 2015 VMP/MPT

CTDa

CTDa Len Dex

2017 VMP CTDa

Kd

Len Dex Pom Dex PVd

Non Intensive

CDF/NICE

2018

VMP UL Kd (velcade

naïve)

CTDa

MPT

(Ixa) len Dex Darzalex Pom Dex

PVd #16

Non Intensive

Trials

MM4 (if minimal

neuropathy and

>PR)

IKEMA

BOSTON

IKEMA

BOSTON

IKEMA

BOSTON

MUK 8

COLUMBA

MUK 8

COLUMBA

MUK 12

Adjuvant Treatment• BISPHOSPHONATES Zoledronate/Pamidronate

• Anti RANKL Denosumab in patient with GFR<15

• Erythropoietin or Transfusion

• G-CSF

• Prophylaxis– Bacterial

– Viral

• ….Clarithromycin

• Venous thrombosis prophylaxis

• Revaccination

• Intravenous Immunoglobulin

Bisphosphonates

• Inhibit osteoclastic breakdown of bone

Bisphosphonates

• Role– acute hypercalcaemia

– Prophylactic to reduce bone pain and fractures and improve survival (5 months)

• Zoledronate monthly (Pamidronate) for at least 24 months….then when disease is active

• Side effects– Hypocalcaemia…..AdCal D3

– Renal

– Osteonecrosis of the jaw following dental extractions

Osteonecrosis of the Jaw

Pain management

Not just due to disease but also due to treatment –

like painful neuropathy

• Paracetamol

• Codeine

• Avoidance of NSAIDS

• Opioids………………try and avoid and reduce asap

• Pregabalin/Duloxetine

• With the patients GP and the pain management

team if needed

Pain management

• Radiotherapy

• Vertebroplasty

• Balloon

Kyphoplasty

• RF kyphoplasty

with tumour

ablation

Longer term complications• Peripheral neuropathy

• Autonomic neuropathy

• Bile Acid Malabsorption

• Constipation

• VTE

• Cord compression

• Unusual sites of relapse

• Amyloidosis affecting unusual places like joints

• ….....plus complications of aging generally

We always need help from allied specialties.

Living with Myeloma

• Quality and not length of life is at the forefront of all decisions

• Support for patients– CNS

– Myeloma patient support group

– Myeloma UK

– MacMillan Cancer nurses

– GP

– Psych/Onc team

– Myeloma doctors…. over many years for most patients

Living with Myeloma

• Holistic assessment

• Discussion of physical, psychological, social

and spiritual needs is carried out on a

regular basis

• ‘Care plan’ for patients

…. end of life care

• Dexamethasone

• Supportive treatments…...or not

• Clinic follow up....or not

• Discussion regarding DNR

• Discussion about hospital admission

• MacMillan team involvement

• Gold standard framework

• Communication with GP

Myeloma: success story

• 2nd most common haematological malignancy but annual incidence is low

• Prevalence has climbed considerably and continues to climb

• ‘Fitter’ older patients

• Many more and much better tolerated treatment options

• Our patients are living longer with myeloma

• Holistic approach to care

Allow patients to live as actively as possible until

death