Download Plasma cell dyscrasias

Plasma cell dyscrasias
Mark Drayson
20
18
16
14
12
10
8
6
4
2
0
Age
<45
45-54
55-64
65-74
75+
%
1.0
5.0
15.4
31.6
47.0
<4
5
45
-4
50 9
-5
4
55
-5
60 9
-6
4
65
-6
70 9
-7
75 4
-7
9
80
-8
85 4
-8
9
90
+
Deaths in age cohort as percentage
total deaths
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
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)
Bone marrow plasma cells IgG, IgA, IgD, IgE, very rarely IgM
Derived from germinal centres lymph nodes, spleen
mutations in variable region gene segments / high affinity
Multiple myeloma
3)
Mucosal plasma cells IgA mostly germinal centre derived
malignancy is rare
4)
Plasma cells from type 1 B cells pleural/peritoneal cavities
Self replenishing from fetal precursors natural antibodies IgM
CLL
Conditions with elevated serum immunoglobulins / paraproteins
Chronic infection, liver disease, HepC, connective tissue disease, HIV, Hodgkins
Post 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
Polyclonal
Immunoglobulin
Small IgG kappa paraprotein
With no immunoparesis
Large IgG lambda paraprotein
With immunoparesis
Immunoparesis in myeloma
IgM (2695 patients)
N.R. 0.5 – 2.0 g/l
<0.5g/l
>0.5g/l
>1.0g/l
>2.0g/l
82%
18%
4.0%
0.8%
IgA and IgM in patients with IgG paraprotein (1498 patients)
N.R.
IgM 0.5 – 2.0 g/l
IgA 0.8 – 4.0 g/l
IgM > 0.5 and IgA > 0.8 11%
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
IgG 6.0 - 16.0 g/l
IgM > 0.5 and IgG > 6.0
IgM > 1.0 and IgG > 10.0
IgM > 2.0 and IgG > 16.0
8.3%
0.7%
0%
IgM, IgA and IgG in patients with light chain myeloma (349 patients)
N.R.
IgM 0.5 – 2.0 g/l
IgG 6.0 - 16.0 g/l
IgM > 0.5 and IgG > 6.0
IgM > 1.0 and IgG > 10.0
IgM > 2.0 and IgG > 16.0
IgA >0.8 IgM > 1.0 and IgG > 10.0
9.7%
0.8%
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 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 attributable to myeloma
A
anaemia 2g/dl below normal or <10g/dl
B
bone lesions lytic or osteoporosis with compression fractue
O
other symptomatic hyperviscosity, amyloidosis,
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
MYELOMA
ASYMPTOMATIC
MYELOMA
MGUS
Bone marrow clonal
plasma cells
In 95% of cases is
>10%
Usually present at
>10%
Often detectable
Always <10%
Serum paraprotein
Present in 80%. No
specific diagnostic
levels
Always present
If 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 group
Summer 2005
Indications for Starting Therapy
1.
Chemotherapy 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
% alive
75
50
31%
25
39%
0
0
1
2
3
4
5
6
7
Years from entry to trial
8
9
10
Relapse free interval from start of plateau phase
100
< 65
65 and over
% relapse free
75
50
25
0
0
1
2
3
4
5
6
Years from plateau
7
8
9
10
Overall survival from progression
100
% alive
75
< 65
65 and over
50
25
0
0
1
2
3
4
5
6
7
Years from progression
8
9
10
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
IL-6, CRP
Specific immunity
TI2 antibody 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
Control patients 11 infections
Septrin
2 infections
p=0.004
•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
2 identical light chains
Either
Kappa
Or
Lambda
(Gene chromosome 14)
(Gene chromosome 2)
(Gene chromosome 22)
Normal plasma cell secretion of
whole immunoglobulin and free light chains
Kappa
Plasma
cells
Lambda
Plasma cells
Production of FLC
Increased malignant FLC
Decreased alternate polyclonal FLC
FLC
BLOOD
FLC
from blood by GF do not alter
Κ/Λ serum FLC ratio
FLC
FL
C
NEOPLASTIC
CLONE
GLOMERULAR
FILTRATION
Changes in removal of FLC
TUBULAR
REABSORPTION
FLC production and filtration
must exceed TR for FLC to
appear in urine
FLC
Therefore altered serum κ/λ FLC ratio
32% of MM patients
have <40mg/l FLC in urine
URINE
FLC
100000
S e rum flc La m bda (m g/L)
10000
1000
Normals
100
10
1
0.1
0.1
1
10
100
1000
Serum flc Kappa (mg/L)
10000
100000
100000
S erum flc La m bda (m g/L)
10000
Normals
1000
Lambda BJ
100
Kappa BJ
10
1
0.1
0.1
1
10
100
1000
Serum flc Kappa (mg/L)
10000
100000
Lancet 2003 361 489-491
100000
Free light chain serum Lambda (mg/L)
Kappa BJM
Lambda BJM
10000
Nonsecretory
myeloma
1000
Normal sera
100
10
1
0.1
0.1
1
10
100
1000
Free light chain serum Kappa (mg/L)
10000
100000
100000
Free light chain serum Lambda (mg/L)
Kappa BJM
Lambda BJM
10000
Nonsecretory
myeloma
AL Amyloidosis
1000
Normal sera
100
10
1
0.1
0.1
1
10
100
1000
Free light chain serum Kappa (mg/L)
10000
100000
Serum free light chain measurements
Diagnosis:
More sensitive than immunofixation (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
% alive
75
χ2=2.52, P=0.11
50
25
0
0
2
4
6
8
Years from entry to trial
10
12
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
CLODRONATE
PLACEBO
100
CLODRONATE
PLACEBO
100
χ2=0.94, P=0.33
χ2=8.24, P=0.004
75
% alive
75
% alive
Overall survival by treatment for those patients presenting with no fractures
50
50
25
25
0
0
0
2
4
6
8
Years from entry to trial
10
12
0
2
4
6
8
Years from entry to trial
10
12
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