Plasma cell dyscrasiasMark Drayson

Mortality statistics for England and Wales. Deaths attributed to multiple myeloma from 1988-1997 by age cohort as a percentage of

total (21,257) deaths

02468

101214161820

<45

45-4

950

-54

55-5

960

-64

65-6

970

-74

75-7

980

-84

85-8

990

+

Age Cohort (years)

Dea

ths

in a

ge c

ohor

t as

perc

enta

ge

tota

l dea

ths

Age % <45 1.045-54 5.055-64 15.465-74 31.675+ 47.0

Types of normal plasma cells

1) Short lived plasma cells found in red pulp of spleenand medullary cords of lymph nodes IgM >>IgG/IgAWaldenstroms

2) Bone marrow plasma cells IgG, IgA, IgD, IgE, very rarely IgMDerived from germinal centres lymph nodes, spleenmutations in variable region gene segments / high affinityMultiple myeloma

3) Mucosal plasma cells IgA mostly germinal centre derivedmalignancy is rare

4) Plasma cells from type 1 B cells pleural/peritoneal cavitiesSelf replenishing from fetal precursors natural antibodies IgMCLL

Conditions with elevated serum immunoglobulins / paraproteins

Chronic infection, liver disease, HepC, connective tissue disease, HIV, HodgkinsPost stem cell rescue, polyclonal/oligoclonal/temporary monoclonal

MGUS monoclonal gammopathy of undetermined significance

Light chain amyloid

Paraprotein neuropathies POEMS etc.

Lymphoplasmacytoid lymphoma (Waldenstroms)

Other B cell NHL (marginal zone lymphoma)

Multiple myeloma

PolyclonalImmunoglobulin

Small IgG kappa paraproteinWith no immunoparesis

Large IgG lambda paraproteinWith immunoparesis

Immunoparesis in myeloma

IgM (2695 patients)N.R. 0.5 – 2.0 g/l <0.5g/l 82%

>0.5g/l 18%>1.0g/l 4.0%>2.0g/l 0.8%

IgA and IgM in patients with IgG paraprotein (1498 patients)

N.R. IgM 0.5 – 2.0 g/l IgM > 0.5 and IgA > 0.8 11%IgA 0.8 – 4.0 g/l IgM > 1.0 and IgA > 2.0 1.4%

IgM > 2.0 and IgA > 4.0 0.2%

IgM and IgG in patients with IgA paraprotein (684 patients)

N.R. IgM 0.5 – 2.0 g/l IgM > 0.5 and IgG > 6.0 8.3%IgG 6.0 - 16.0 g/l IgM > 1.0 and IgG > 10.0 0.7%

IgM > 2.0 and IgG > 16.0 0%

IgM, IgA and IgG in patients with light chain myeloma (349 patients)

N.R. IgM 0.5 – 2.0 g/l IgM > 0.5 and IgG > 6.0 9.7%IgG 6.0 - 16.0 g/l IgM > 1.0 and IgG > 10.0 0.8%

IgM > 2.0 and IgG > 16.0 0%IgA >0.8 IgM > 1.0 and IgG > 10.0 8.0%

Criteria for the classification of monoclonal gammopathies,multiple myeloma and related disorders

International Myeloma Working Group

B. J Haem 2003, 121 749-757

MGUS•M-protein in serum <30g/l

•Bone marrow plasma cells <10%low level infiltration in trephine biopsy

•No evidence of other B-cell proliferative disorder

•No related organ or tissue impairment

MGUS a paraprotein with no evidence of related disease

Prevalence >50yrs 1% >70yrs 3%

70% IgG, 12% IgA and 15% IgM

38% have immune paresis

31% have free light chains in urine

MGUS associated with amyloidMGUS associated with paraprotein related neurological syndromes

A long-term study of prognosis in monoclonal gammopathy of undetermined significance.N Engl J Med. 2002 Feb 21;346(8):564-9.

1384 patients 11,009 years follow up 1960 – 1994

115 progressed – relative risk 7.3 (25 MM, 46 Waldenstroms, 2 IgMlymphoma, 8 primary amyloid, 0.9 CLL)

actual risk >1% per year (12% at 10 years, 30% at 25 years)

Initial paraprotein concentration and IgM/IgA versus IgG only significant prognostic indicators.Paraprotein level 10 year risk of progression to disease:-

<5g/l 6%15g/l 11%20g/l 20%25g/l 24%30g/l 34%

Symptomatic myelomaMust have evidence of related organ or tissue impairment (ROTI)C calcium >0.25mmol/l above normal / >2.75mmol/lR renal impairment attributable to myelomaA anaemia 2g/dl below normal or <10g/dlB bone lesions lytic or osteoporosis with compression fractueO other symptomatic hyperviscosity, amyloidosis,

recurrent bacterial infectionWith •Bone marrow clonal plasma cells (usually>10%)•M-protein in serum and / or urine (usually)

Asymptomatic myelomaNo evidence of end-organ damage with both:•Bone marrow plasma cells >10%•M-protein in serum and or urine

-

SYMPTOMATIC MYELOMA

ASYMPTOMATIC MYELOMA

MGUS

Bone marrow clonal plasma cells

In 95% of cases is>10%

Usually present at>10%

Often detectableAlways <10%

Serum paraprotein Present in 80%. No specific diagnostic levels

Always presentIf plasma cells <10% then >30g/l

Always present<30 g/l

Bence-Jones proteinuria

Present in 70%15 – 20% no serum paraprotein

Present in >50% Present in 30%

Immune paresis Present in >80% Present in >50% Present in 40%

Symptoms Present in 85% Absent Absent

Myeloma related organ dysfunction

Always present Absent Absent

UK Guidelines on the diagnosis and management of multiple myeloma.Br J Haematol. 2001 Dec;115(3):522-40. BCSH and UK MF

BSH Website

Up-dated with NORDIC groupSummer 2005

Indications for Starting Therapy

1. Chemotherapy is indicated for management of symptomatic myeloma

2. Chemotherapy is not indicated for patients with MGUSor those with asymptomatic myeloma (equivocal/indolent/smouldering).Patients with no symptoms, normal Hb, calcium and renal functionand no bone lesions may remain stable for a long period without treatment.Early intervention has shown no benefit in 2 randomised controlled trials(Hjorth. 1993; Riccardi et al 2000).

Overall survival by age and by plateau status

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10Years from entry to trial

% a

live

> 65yrs - 428 patients

< 65yrs - 571 patients

39%

31%

Relapse free interval from start of plateau phase

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10

Years from plateau

% r

elap

se fr

ee

< 6565 and over

Overall survival from progression

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10Years from progression

% a

live

< 6565 and over

Infection in myeloma

Respiratory tract encapsulated pyogenic bacteria

Incidence 14% in year before diagnosis25% in first 3 months10% per patient year in plateau

Innate immunityIL-6, CRP

Specific immunityTI2 antibody responses

Intravenous immunoglobulin replacement

First 3 monthsMRC IVIg trial 203 patients no significant benefit

?Problems with innate immunity predominate

Antibiotic prophylaxis in first 3 months•reduce morbidity / mortality from infection

Am J Med 1996 - 54 patients first 3 months p=0.004Control patients 11 infectionsSeptrin 2 infections

•Reduce disease activity by reducing infection induced IL-6 levels?

Intravenous immunoglobulin replacement

Plateau phase82 patients Chapel et al Lancet 1994 p = 0.019

Placebo 38 infections in 470 patient monthsIVIg 19 infections in 449 patient months

Vaccination in plateau5 studies (13 – 52 patients per trial)Pneumovax (TI2) 20% normal responseHaemophillus conj (TD) normal responses

Study of Hib and new pneumococcal conjugate vaccineIn plateau phase?

Immunoglobulin2 identical heavy chains (Gene chromosome 14)2 identical light chainsEither Kappa (Gene chromosome 2)Or Lambda (Gene chromosome 22)

Normal plasma cell secretion ofwhole immunoglobulin and free light chains

KappaPlasmacells

LambdaPlasma cells

Production of FLCIncreased malignant FLCDecreased alternate polyclonal FLC

BLOODFLC

NEOPLASTICCLONE

FLC

GLOMERULARFILTRATION

TUBULARREABSORPTION

URINEFLC

FLC

FLC

FLC

Changes in removal of FLCfrom blood by GF do not alterΚ/Λ Κ/Λ Κ/Λ Κ/Λ serum FLC ratio

FLC production and filtrationmust exceed TR for FLC toappear in urine

32% of MM patientshave <40mg/l FLC in urine

Therefore altered serum κ/λκ/λκ/λκ/λ FLC ratio

0.1

1

10

100

1000

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100000

0.1 1 10 100 1000 10000 100000

Serum flc Kappa (mg/L)

Ser

um fl

c La

mbd

a (m

g/L)

Normals

0.1

1

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100000

0.1 1 10 100 1000 10000 100000

Serum flc Kappa (mg/L)

Ser

um fl

c La

mbd

a (m

g/L)

Normals

Lambda BJ

Kappa BJ

Lancet 2003 361 489-491

0.1

1

10

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0.1 1 10 100 1000 10000 100000

Free light chain serum Kappa (mg/L)

Fre

e lig

ht

chai

n s

eru

m L

amb

da

(mg

/L)

Kappa BJM

Lambda BJM

Nonsecretorymyeloma

Normal sera

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10

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0.1 1 10 100 1000 10000 100000

Free light chain serum Kappa (mg/L)

Fre

e lig

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chai

n s

eru

m L

amb

da

(mg

/L)

Kappa BJM

Lambda BJM

Nonsecretorymyeloma

AL Amyloidosis

Normal sera

Serum free light chain measurements

Diagnosis: More sensitive than immunofixation (10-100x)No problem with renal threshold1/3 patients with no detectable urinary FLCFLC only myeloma, Non-secretory myelomaAmyloidosis

Monitoring: Not confounded by changes in renal function

Rapid response to changes in tumour loadbecause of short half life (hours)

More sensitive (What is a complete response?)

Observations of the MRC Myelomatosis Trials

IVth MP vs MVP 3 litres of fluid per day

Vth M7 vs ABCM 316 / 314 P=0.003

VIth ABCM vs ABCMP 343 / 342 P=0.11

VIIIth ABCM vs ABCM/CW 536

Bisphosphonates reduce skeletal morbidity

Interferon in prolongs plateau phase but not overall survival

Overall survival by treatment

0

25

50

75

100

0 2 4 6 8 10 12Years from entry to trial

% a

live

ABCMABCMP

χχχχ2=2.52, P=0.11

The clodronate trial showed:•Reduced morbidity from skeletal disease•Patients (155) without overt skeletal disease at presentationappeared to benefit more than patients with fractures at presentation•No overall survival benefit

Overall survival by treatment

0

25

50

75

100

0 2 4 6 8 10 12Years from entry to trial

% a

live

CLODRONATEPLACEBO

χχχχ2=0.94, P=0.33

Overall survival by treatment for those patients presenting with no fractures

0

25

50

75

100

0 2 4 6 8 10 12Years from entry to trial

% a

live

CLODRONATEPLACEBO

χχχχ2=8.24, P=0.004

Non-intensive treatmentMelphalan +/- prednisoloneABCM

Intensive treatmentVAD / CVAMP (avoid stem cell damage)Then high dose melphalan with PBSCT mortality <5%

Allogeneic high mortality 20% - 38%

Interferon in plateau phase - probably not

Intensive versus conventional chemotherapy

New England J Med 2003 348 1875 - 83

THALIDOMIDE

MONOCLONALS

MINI-ALLOGRAFTS

PROTEASOME INHIBITORS

MRC 9Clodronate / zoledronateCVAD / CTD or MP / CTDThalidomide maintenance

MERITRandomisation to plasma exchange