Plasma cell dyscrasias Mark Drayson

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1 Plasma cell dyscrasias Mark Drayson

2 Mortality statistics for England and Wales. Deaths attributed to multiple myeloma from by age cohort as a percentage of total (21,257) deaths Deaths in age cohort as percentage total deaths Age % < < Age Cohort (years)

3 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

4 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

5 Polyclonal Immunoglobulin

6 Small IgG kappa paraprotein With no immunoparesis Large IgG lambda paraprotein With immunoparesis

7 Immunoparesis in myeloma IgM (2695 patients) N.R 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 g/l IgM > 0.5 and IgA > % IgA g/l IgM > 1.0 and IgA > % IgM > 2.0 and IgA > %

8 IgM and IgG in patients with IgA paraprotein (684 patients) N.R. IgM g/l IgM > 0.5 and IgG > % IgG g/l IgM > 1.0 and IgG > % IgM > 2.0 and IgG > % IgM, IgA and IgG in patients with light chain myeloma (349 patients) N.R. IgM g/l IgM > 0.5 and IgG > % IgG g/l IgM > 1.0 and IgG > % IgM > 2.0 and IgG > % IgA >0.8 IgM > 1.0 and IgG > %

9 Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders International Myeloma Working Group B. J Haem 2003,

10 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

11 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

12 A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med Feb 21;346(8): patients 11,009 years follow up 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%

13 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

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15 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

16 UK Guidelines on the diagnosis and management of multiple myeloma. Br J Haematol Dec;115(3): BCSH and UK MF BSH Website Up-dated with NORDIC group Summer 2005

17 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).

18 Overall survival by age and by plateau status < 65yrs patients > 65yrs patients % alive % 0 39% Years from entry to trial

19 Relapse free interval from start of plateau phase 100 % relapse free < and over Years from plateau

20 Overall survival from progression < and over % alive Years from progression

21 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

22 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 patients first 3 months Control patients 11 infections Septrin 2 infections p=0.004 Reduce disease activity by reducing infection induced IL-6 levels?

23 Intravenous immunoglobulin replacement Plateau phase 82 patients Chapel et al Lancet 1994 p = 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?

24 Immunoglobulin 2 identical heavy chains (Gene chromosome 14) 2 identical light chains Either Kappa (Gene chromosome 2) Or Lambda (Gene chromosome 22) Normal plasma cell secretion of whole immunoglobulin and free light chains Kappa Plasma cells Lambda Plasma cells

25 Production of FLC Increased malignant FLC Decreased alternate polyclonal FLC NEOPLASTIC CLONE FLC GLOMERULAR FILTRATION FLC Changes in removal of FLC from blood by GF do not alter Κ/Λ serum FLC ratio FLC BLOOD FLC TUBULAR REABSORPTION FLC FLC production and filtration must exceed TR for FLC to appear in urine Therefore altered serum κ/λ FLC ratio 32% of MM patients have <40mg/l FLC in urine URINE FLC

26 S erum flc Lambda (mg/l) Normals Serum flc Kappa (mg/l)

27 Normals S erum flc Lambda (mg/l) Lambda BJ Kappa BJ Serum flc Kappa (mg/l) Lancet

28 Kappa BJM Free light chain serum Lambda (mg/l) Lambda BJM Nonsecretory myeloma Normal sera Free light chain serum Kappa (mg/l)

29 Kappa BJM Free light chain serum Lambda (mg/l) Lambda BJM Nonsecretory myeloma AL Amyloidosis Normal sera Free light chain serum Kappa (mg/l)

30 Serum free light chain measurements Diagnosis: Monitoring: 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 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?)

31 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

32 Overall survival by treatment 100 ABCM ABCMP 75 χ2=2.52, P=0.11 % alive Years from entry to trial

33 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 PLACEBO 100 CLODRONATE PLACEBO 75 χ2=0.94, P= χ2=8.24, P=0.004 % alive 50 % alive Years from entry to trial Years from entry to trial

34 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

35 Intensive versus conventional chemotherapy New England J Med

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38 THALIDOMIDE MONOCLONALS MINI-ALLOGRAFTS PROTEASOME INHIBITORS MRC 9 Clodronate / zoledronate CVAD / CTD or MP / CTD Thalidomide maintenance MERIT Randomisation to plasma exchange