Plasma cell dyscrasias Mark Drayson Mortality statistics for England and Wales. Deaths attributed to from 1988-1997 by age cohort as a percentage of total (21,257) deaths

e 20 g a t 18 n

e Age % c 16 r <45 1.0 e

p 45-54 5.0 14 s s 55-64 15.4 h a

t

t 12 a r 65-74 31.6 e o

d 75+ 47.0 h

10 l o a c t

o 8 e t g a

6 n i

s 4 h t a 2 e

D 0 5 9 4 9 4 9 4 9 4 9 + 4 -4 -5 -5 -6 -6 -7 -7 -8 -8 0 < 5 0 5 0 5 0 5 0 5 9 4 5 5 6 6 7 7 8 8 Age Cohort (years) Types of normal plasma cells

1) Short lived plasma cells found in red pulp of spleen and medullary cords of lymph nodes IgM >>IgG/IgA Waldenstroms

2) plasma cells IgG, IgA, IgD, IgE, very rarely IgM Derived from germinal centres lymph nodes, spleen in variable region gene segments / high affinity Multiple myeloma

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

4) Plasma cells from type 1 B cells pleural/peritoneal cavities Self replenishing from fetal precursors natural IgM CLL Conditions with elevated serum immunoglobulins / paraproteins

Chronic infection, liver disease, HepC, connective tissue disease, HIV, Hodgkins Post rescue, polyclonal/oligoclonal/temporary monoclonal

MGUS of undetermined significance

Light chain amyloid

Paraprotein neuropathies POEMS etc.

Lymphoplasmacytoid (Waldenstroms)

Other NHL (marginal zone lymphoma)

Multiple myeloma Polyclonal Immunoglobulin Small IgG kappa paraprotein Large IgG lambda paraprotein With no immunoparesis With 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- 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 amyloid MGUS 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 IgM lymphoma, 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 myeloma Must have evidence of related organ or tissue impairment (ROTI) C calcium >0.25mmol/l above normal / >2.75mmol/l R renal impairment attrib-utable to myeloma A anaemia 2g/dl below normal or <10g/dl B bone lesions lytic or osteoporosis with compression fractue O other symptomatic hyperviscosity, , recurrent bacterial infection With •Bone marrow clonal plasma cells (usually>10%) •M-protein in serum and / or urine (usually)

Asymptomatic myeloma No evidence of end-organ damage with both: •Bone marrow plasma cells >10% •M-protein in serum and or urine

SYMPTOMATIC ASYMPTOMATIC MGUS MYELOMA MYELOMA

Bone marrow clonal In 95% of cases is Usually present at Often detectable plasma cells >10% >10% Always <10%

Serum paraprotein Present in 80%. No Always present Always present specific diagnostic If plasma cells <10% <30 g/l levels then >30g/l

Bence-Jones Present in 70% Present in >50% Present in 30% 15 – 20% no serum paraprotein

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

Symptoms Present in 85% Absent Absent

Myeloma related Always present Absent Absent organ dysfunction 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 group Summer 2005 Indications for Starting Therapy

1. is indicated for management of symptomatic myeloma

2. Chemotherapy is not indicated for patients with MGUS or those with asymptomatic myeloma (equivocal/indolent/smouldering). Patients with no symptoms, normal Hb, calcium and renal function and 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

100 < 65yrs - 571 patients

> 65yrs - 428 patients 75 e v i l a 50

%

25 31%

39% 0 0 1 2 3 4 5 6 7 8 9 10 Years from entry to trial Relapse free interval from start of plateau phase 100

75 < 65 e 65 and over e r f e s

p 50 a l e r

% 25

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

100

75 < 65 65 and over e v i l

a 50

%

25

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

Respiratory tract encapsulated pyogenic bacteria

Incidence 14% in year before diagnosis 25% in first 3 months 10% per patient year in plateau

Innate immunity Specific immunity IL-6, CRP TI2 responses Intravenous immunoglobulin replacement

First 3 months MRC 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=0.004 Control patients 11 infections Septrin 2 infections •Reduce disease activity by reducing infection induced IL-6 levels? Intravenous immunoglobulin replacement

Plateau phase 82 patients Chapel et al Lancet 1994 p = 0.019 Placebo 38 infections in 470 patient months IVIg 19 infections in 449 patient months

Vaccination in plateau 5 studies (13 – 52 patients per trial) Pneumovax (TI2) 20% normal response Haemophillus conj (TD) normal responses

Study of Hib and new pneumococcal conjugate vaccine In plateau phase? Immunoglobulin 2 identical heavy chains (Gene ) 2 identical light chains Either Kappa (Gene chromosome 2) Or Lambda (Gene )

Normal secretion of whole immunoglobulin and free light chains

Kappa Plasma cells Lambda Plasma cells Production of FLC Increased malignant FLC Decreased alternate polyclonal FLC Changes in removal of FLC from blood by GF do not alter Κ/Λ serum FLC ratio GLOMERULAR NEOPLASTIC FILTRATION FLC C L F TUBULAR FLC production and filtration REABSORPTION must exceed TR for FLC to BLOOD FLC appear in urine FLC FLC

Therefore altered serum κ/λ FLC ratio 32% of MM patients have <40mg/l FLC in urine

URINE FLC 100000

10000 ) L / g m

( 1000 Normals a d b

m 100 a L

c l f 10 m u r e S 1

0.1 0.1 1 10 100 1000 10000 100000

Serum flc Kappa (mg/L) 100000

10000 Normals ) L / g

m 1000 Lambda BJ (

a d b

m 100 Kappa BJ a L

c l f

m 10 u r e S 1

0.1 0.1 1 10 100 1000 10000 100000

Serum flc Kappa (mg/L) Lancet 2003 361 489-491 100000 Kappa BJM ) L / Lambda BJM g 10000 m ( Nonsecretory a

d myeloma b 1000 m Normal sera a L m u r 100 e s n i a h

c 10 t h g i l e

e 1 r F

0.1 0.1 1 10 100 1000 10000 100000 Free light chain serum Kappa (mg/L) 100000 Kappa BJM

) Lambda BJM L / 10000 g Nonsecretory m

( myeloma

a AL Amyloidosis d b 1000 Normal sera m a L m u

r 100 e s n i a h

c 10 t h g i l e

e 1 r F

0.1 0.1 1 10 100 1000 10000 100000 Free light chain serum Kappa (mg/L) Serum free light chain measurements

Diagnosis: More sensitive than (10-100x) No problem with renal threshold 1/3 patients with no detectable urinary FLC FLC only myeloma, Non-secretory myeloma Amyloidosis

Monitoring: Not confounded by changes in renal function

Rapid response to changes in tumour load because 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

100 ABCM ABCMP

75 χ2=2.52, P=0.11 e v i l

a 50

%

25

0 0 2 4 6 8 10 12 Years from entry to trial The clodronate trial showed: •Reduced morbidity from skeletal disease •Patients (155) without overt skeletal disease at presentation appeared to benefit more than patients with fractures at presentation •No overall survival benefit

Overall survival by treatment Overall survival by treatment for those patients presenting with no fractures

100 CLODRONATE 100 CLODRONATE PLACEBO PLACEBO

χ2=0.94, P=0.33 χ2=8.24, P=0.004 75 75 e v e i l v i l a 50

a 50

% %

25 25

0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Years from entry to trial Years from entry to trial Non-intensive treatment Melphalan +/- prednisolone ABCM

Intensive treatment VAD / 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 9 Clodronate / zoledronate CVAD / CTD or MP / CTD Thalidomide maintenance

MERIT Randomisation to plasma exchange