Myeloma Primary Care. Dr R Lovell Feb 2015

Transcription

1 Myeloma Primary Care Dr R Lovell Feb 2015

2 Aims Balance of pathophysiology and cases Explain diagnostic changes (minimal) Staging UK influence Autologous stem cell transplants Primary care myeloma problems

3 Why I love blood!

4 Plasma cell differentiation

5 Plasma cell disorders identified by presence of a single immunoglobulin in excess the Monoclonal protein or paraprotein and/or light chain component (non-secretory disease is very rare) Kappa κ Lambda λ

6 Monoclonal Gammopathy of Undetermined Significance (MGUS, ICD-O /1): Average Number of New Cases per Year and Age-Specific Incidence Rates, UK estimates based on data from HMRN region Original data sources: Prepared by Cancer Research UK Haematological Malignancy Research Network.

7 Normal FBC Renal Ca No bone lesions Rest of Igs normal Paraprotein <30 MGUS SFLC ratio and B2m normal low risk

8 Monoclonal gammopathy of uncertain significance No evidence of end organ damage (anaemia, high calcium, renal failure, infection, bone pain or lesion) Monoclonal protein is less than 30g/L (3g/dL) Less than 10% plasma cells in the bone marrow IT IS COMMON AND RELATED TO AGEING (>5% over 80 years of age) RISK OF PRGRESSION is low = around 1% per year for an individual RISK OF PROGRESSION stays the same each year MGUS is associated with an increased infection risk, osteoporosis and rarely with renal disease (monoclonal gammopathy of renal significance)

9 Light chain only MGUS does exist 15-20% of myelomas are light chain only Only found if serum free light chains or urine light chain analysis done THEREFORE rarely found Approximately 0.5-1% of population >50 years have light chain only MGUS (Dispenzieri et al, 2010) Rate of progression to myeloma, AL amyloid probably less than that for intact immunoglobulin MGUS (perhaps <0.5% per year)

10 Mr PS Age 72 TATT Hb 146 Wcc 6.8 PLts 268 Cr, U, Ca2+, all normal IgG 16 IgA IgM normal SS OA changes only MGUS

11 Myeloma patients in asymptomatic patients without CRABI = asymptomatic or smouldering myeloma until this revision in 2014 Patients with the highest risk asymptomatic multiple myeloma should be treated These include Patients with >60% bone marrow plasma cell infiltrate (2-3% of patients) Patients with serum free light chain ratio >100 (7-15% of patients) Patients with >1 lesion on whole body MRI scan (15% of patients) as risk of progression is >80% at 2 years

12 Lytic lesion (not sclerotic like breast cancer or other tumours)

13 Screening for plasma cell disorders Immunoglobulins = laboratory will do serum electrophoresis (and if find a peak suggestive of a monoclonal protein will do immmunofixation and densitometry) AND Serum free light chains (or urine for Bence Jones protein) Only exception is rare cases of AL amyloidosis have been reported where FLC only detectable in urine with no abnormality in serum so URINE for FLC needed if AL amyloid suspected but no M-protein or FLC in serum Urinalysis is not necessary for screening for myeloma

14 Often a delay in suspecting myeloma 50.6% of myeloma patients visited their primary care doctor three or more times before hospital referral in the UK At least 33% present via emergency admission

15 Myeloma pathophysiology

16 Myeloma 2 nd commonest haem malignancy Longest delays in diagnosis Indolent Malignant growth plasma cells Plasma cells terminally differentiate B cells Paraprotein Increase light chains Bone destruction Renal failure Bone marrow failure (low Hb low WCC low Plts) Spectrum of disease MGUS vs PCL Still incurable Rates increasing

17 Bone disease and destruction (40-70%) Osteoclast activity is increased, causing increased reabsorption Osteoblast activity is decreased and cannot keep up with the osteoclast activity. This results in lytic lesions and hypercalcaemia NB cytokines implicated in the above not only increase osteoclast activity but also stimulate myeloma cell growth

18 Myeloma

19 Anaemia, fatigue and infection 10-60% Physical inhibition of normal haemopoesis Myeloma cells secrete inhibitory cytokines (TNF, IL-1) also contributing Leucopenia Aetiology of fatigue is not fully understood but it can be caused by anaemia, renal failure, psychological factors. It is not relieved by rest

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21 Myeloma diagnosis minor changes Plasmacytosis in marrow (if >60% nil else) Paraprotein / SFLC End organ damage CRAB New parameters for bone lesions and cut offs for SFLC

22 International staging system Stage III=B2m >5.5 Stage II= not others Stage I=B2m <3.5 Alb >35 JCO MAY 20, 2005 VOL. 23 NO

23 Myeloma (C90): Average Number of New Cases Per Year and Age-Specific Incidence Rates per 100,000 Population, UK Prepared by Cancer Research UK - original

24 Myeloma (C90): European Age-Standardised Incidence Rates per 100,000 Population, by Age, Persons, Great Britain

25 Treatments First line Stem cell transplantation Radiotherapy Second/third line treatments Maintenance Supportive care Novel therapies

26 Bisphosphonates Bisphosphonates Relieve pain by binding to the bone surface, reducing destruction and may aid repair Gold standard IV Zolendronate Dose adjust in renal failure Clear evidence from MM IX trial has an antimyeloma effect

27 NICE?

28 Myeloma NICE The good the bad and the ugly Messed with myeloma from the start Mostly helped standardised use of novel agents Draft guidelines Nov 2014

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30 Myeloma Over 4,500 new myelomas are diagnosed each year in the UK. A full time GP is likely to diagnose approximately 2-3 people with myeloma in their career. Five year survival is nearly 50%. They looked at all symptoms in elderly >60yrs No common single factor When combined with hypercalcaemia OR leucopenia often correlation Offer very urgent electrophoresis <48hrs!!

31 Myeloma my clues Bone pain/fracture high Ca = myeloma Renal failure high calcium = myeloma High protein low albumin = paraprotein Low / suppressed IGs = myeloma OR severe cachexia Cost Igs screen = 1 rest of tests 80p Cost of Lenalidomide 1 year 52 K!

32 JF Presented in Oct 2001 to A&E with Acute renal failure Extensive bony pains throughout the body Fatigue

33 JF Investigations showed Hb:4.0 WBC:9.6 N:6.8 PLT:442 Urea:54 Creat:1172 K:5.7 Ca:2.6 B2M:32 Alb:40

34 JF No paraprotein detected Urine for BJP + Skeletal survey : multiple lytic lesions BMA: 50% plasma cells Diagnosis: Multiple Myeloma

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40 JF HD R femoral nailing Intensive chemo Bisphosphonate DXT

41 JF 4x bolus VAD July2002 PBSCHarvest 3/12 Cyclophosphamide Relapsed March04 Reinduction 2xVAD Mel140 PBSCT 2nd plateau

42 JF Monitored with serum free light chain assay Remission for almost 20 months Relapsed February 2006 Started Melphalan reduced dose-poor response

43 JF DXT for shoulder pain Thalidomide and Dexamethasone no significant improvement Recently added cyclophosphamide PCT have turned down Velcade

44 Light chain assay kappa and lamda k/l ratio k l k/l Apr 11/11/ /9/2006 8/8/2006 7/7/2006 5/5/2006 1/1/2006 9/9/2005 4/4/ /12/ /11/ /10/ k l k/l date

45 Conclusions Light chain myeloma 15% of myeloma patients Renal failure 80% Serum free light chain assay important JF ISS 3 predicted survival 29/12 JF now survived 72/12

46 Conclusions Incurable terminal disease Auto PBSCT used for disease control not curative VAD followed by SCharvest was gold std Relapse treatment

47 Overall survival from diagnosis of multiple myeloma. Kumar S K et al. Blood 2008;111:

48 Induction Aim get the best remission with least toxicity Why CR patients have longer PFS OS MM XI Bortezomib based Pethema group high risk Meta analysis suggests benefit DTPACE for PCL

49 Why auto? History MM VII

50 ASCT group myeloma VII (n = 200) Proportion surviving MR PR CR Number at risk Survival in months MR PR CR Child et al. NEJM 2003;348:

51 Conclusion MM IX Conventional paraprotein response 100% 80% 60% 40% 20% NR PR VPR CR 0% Induction: CVAD Induction: CTD Day 100: CVAD Day 100: CTD

52 Myeloma IX CTD non-inferior to CVAD for PFS and OS. Morgan et al 2012 Haematologica

53 Maintenance / Consolidation Zolendronic acid scr CR VGPR MR SD Toxicity vs. efficacy Nordic group Bortezomib Thal meta analysis Lenalidomide await M XI Safety / QOL leave this area unclear

54 Maintenance in Myeloma: Still a Work in Progress? Provides PFS advantage Longer follow-up needed OS improvements noted Toxicities of treatment Myelosuppression Second primary malignancies Quality of life Unknown response to higher doses of lenalidomide at relapse; potential development of resistant clones Observation is still an option Unclear whether all patients benefit from maintenance Tailor treatment choice to individual patient Van de Donk N, et al. Cancer Management Res. 2012;4:

55 a. Monitoring remember light chain IgAλ paraprotein Serum lambda FLC Velcade escape Serum lambda FLC (mg/l) IgA paraprotein (g/l) Time (days) Courtesy of Effie Liakopoulou, Christies Hospital

56 2 nd Auto why? MM X

57 History 61yr male ISS Stage 2 MM CTD x2 in MM9 Increasing SOB O/E Sats 92% Temp 38

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60 Answers CMV copies /ml blood Bronchoscopy CMV lavage Treated Ganci 14/7 Complete resolution

61 Myeloma & CMV Little known in detail Not routinely monitored / screened Up to 50% of late non neutropenic fevers post auto can be CMV viraemia

62 Primary care Lenalidomide LFTs, diarrhoea, SCC secondary malignancies Carfilzomib LVF Dexamethasone Usual but 40mg per day Cyclophosphamide Usually well tolerated low counts N&V

63 Conclusion Think myeloma Over 4,500 new myelomas are diagnosed each year in the UK. A full time GP is likely to diagnose approximately 2-3 people with myeloma in their career. Five year survival is nearly 50%. Simple tests BUT at all answers Cheap and easy often automated Any questions!!