Myeloma for Diagnosticians Dr Mamta Garg Consultant Haematologist What is Myeloma? Malignant disorder of plasma cells • an excess of abnormal plasma cells >10% • paraprotein in the serum and/or urine • End organ affection CRAB, SLiM CRAB Diagnosis: Paraprotein or M protein SPEP CRAB and now “Slim CRAB” • Myeloma defining events or Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: – C: Hypercalcaemia: serum calcium >0·25 mmol/L higher than the upper limit of normal or >2·75 mmol/L R: Renal insufficiency – R: Creatinine clearance <40 mL per min or serum creatinine >177 μmol/L (>2 mg/dL) – A: Anaemia: Hb >20 g/L below usual Hb, or a Hb <100 g/L – B: Bone lesions: one or more osteolytic lesions on XR, CT or PET-CT • Any one or more of the following biomarkers of malignancy: – S (M-spike) : Clonal bone marrow plasma cell percentage* ≥60% – Li: Involved:uninvolved serum free light chain ratio≥100 (or <0.01) – M: >1 focal lesions on MRI studies of 1 cm in size Rajkumar et al. Lancet Oncol. 2014 Nov;15(12):e538-48 Asymptomatic/Smouldering Myeloma • M protein present in serum and/or urine • Plasma cells >10% in the marrow • No CRABs • It carries a higher risk of progression to frank multiple myeloma (10% per year the first 5 years) compared with MGUS ISS, now Revised ISS or R-ISS LDH and FISH analysis on BM sample mandatory ISS STAGE CRITERIA RISK CRITERIA I B2M <3.5 Albumin >35 Normal Normal Serum LDH <upper limit of normal II B2M >3.5 but <5.5 or Albumin <35 High High serum LDH >255 for us III B2M >5.5 R-ISS STAGE CRITERIA I ISS I and standard risk cytogenetic abnormality and RISK CRITERIA normal LDH Standard No high risk chromosomal II Not R-ISS I or III abnormalities (CA) III ISS stage IIIand either high risk High Risk T(4:14), t(14:16) del 17p Iq CA by iFISH or high LDH gains, Ip loss and t(16:20) IMWG report Palumbo et al JCO Aug 3 2015 61 2267 Munshi et al IMWG panel 2 consensus recommendations for risk stratification Blood 2011 117 4696 -4700 R-ISS risk stratify and helps to prognosticate ISS CA High R-ISS PFS m OS m Non Tx Tx iMiD PI LDH based I No No I 66 NR 66 NR NR NR I Y/N Y/N II 42 83 70 88 88 81 (8 yrs) II II 42 83 70 88 88 81 III y/N Y/N III 29 43 41 42 40 47 (3.5 y) IMWG report Palumbo et al JCO Aug 3 2015 61 2267 Munshi et al IMWG panel 2 consensus recommendations for risk stratification Blood 2011 117 4696-4700 Age-specific incidence rates by age group for myeloma in males and females between 2006-2008 in England NCIN. Haematological malignancies in England 2001-2008 Demographics • Myeloma is a disease of the elderly • In UK median age at diagnosis 73 years • Latest USA registry data: 55% are ≥ age 75 (1975-2010) • More and more patients >87 years • Incidence: 65-70 new symptomatic cases per year in Leicester (68/million) • Additional 10 Asymptomatic myeloma per year Changing demographics • Incidence and prevalence of myeloma expected to rise – Aging population predicted increased incidence of 57% between 2010-2030 – Better GP and medical education, high index of suspicion leads to earlier diagnosis – Improved survival with novel therapies from 3.5 years to 10 years • therefore increased prevalence – Disease biology is different in very elderly myeloma – sometimes responds to dexamethsone alone giving patients survival of >12m – it is difficult to tell clinicians not to test/diagnose over 90 – Treated up to 97 years of age with steroids alone above 90 years age Natural course of disease 1st line 2nd line 3rd line treatment treatment treatment MGUS: Monoclonal gammopathy of undetermined significance Survival improving Shahjikumar Leukemia(2017) 1915–1921 Presentation • De novo or following MGUS - <5% • Bone problems – Back pain – Spinal cord compression – Pathological fracture • Renal Failure • Recurrent infections • Anaemia….often macrocytic • Chance finding…............ACR:PCR discrepancy on diabetic review Who diagnoses/suspect Myeloma in Leicestershire • 90 consecutive NDMM patients assessed – symptomatic • 33 from GP – 20 backache – 17 anaemia – 3 high ca – 4 AKI – 2 urine PCR and ACR discrepancy • 34 from medics: a/w high ca, full house, AKI, anaemia, sepsis, radiology flag, skeletal lesions • 12 Renal team with AKI and Igs is part of workup • 5 radiology flag • 3 spinal surgeon/orthopaedics • 3 from MGUS or AMM monitoring – raises concern over monitoring practices Presentation • Back pain is the 2 nd most common complaint in primary care • <1% of patients presenting with back pain will have a malignant cause • Back pain is the most common complaint in myeloma presentation (58%) • Anaemia and any other abnormal blood parameter with back pain was highly predictive of ‘high risk’ back pain • Average 11 months Time to diagnose from various pointers in blood test J Am Board Fam Med November-December 2016 vol. 29 no. 6 702-709 Immunoglobulin molecule Light chains are small molecules Kappa ~ 25kDa Lambda ~ 50 kDa Can pass through GBM, reabsorbed and metabolised in proximal convoluted tubules Capacity up to 500 mg/day In Myeloma if the light chains are produced in excess then the capacity to be reabsorbed in PCT is overcome and Light chains appear in urine (Bence Jones Proteinuria) Urine protein and albumin • Normally there should be no protein in the urine. • Particles with a molecular mass of >60kDa cannot filter through the glomerular basement membrane (GBM) • Albumin is 66.5 kDa cannot filter through glomerulus unless there is a structural damage to the glomeruli for ex in diabetic nephropathy • Commonly found proteins in the urine are • Albumin in disease state in glomerular diseases • free light chains in myeloma/MGUS (also called urinary bence jones UBJ) • haemoglobin or myoglobin in specific disease states • B2 Microglobulin • Normal tubular protein like tams-horsfall protein <0.15 g/d • Total urinary protein excretion in the normal adult < 150mg/day • Total Albumin excretion should be < 30mg/day. • http://bestpractice.bmj.com/best-practice/monograph/875.html Urine PCR and ACR – usual report • Normal Levels • Urine PCR 0-30 mg/mmol • Urine ACR 0-2.5 mg/mmol creatinine • Urine Protein < 0.15 g/L • Urine Albumin 0-15 mg/L • PCR is raised in both BJ proteinuria as well as Albuminuria • ACR is only raised in albuminuria • Normally they are concordant as commonest disease state is albuminuria like in diabetes • When discordant then alarm bells should be ringing for myeloma • Like .. Case History to illustrate SB, 71 years female, presented with free light chain myeloma in June 2014 Free lambda on SPEP electrophoresis was 9.1 g/L (normal no band) Free lambda on serum freelite assay was 23,660 mg/L (normal range 5.7- 26.3) Her Urine PCR and ACR and serum creatinine in the preceding 2 years were as follows: 09/06/14 30/09/13 21/08/12 Urine PCR (0-30) 1312 1317 476 Urine ACR (0-2.5) 16.3 10.7 Urine Protein (<0.15) 5.51 g/L 6.32 g/L 3.62 g/L Urine albumin (0-15) 78 mg/L 81 mg/L Hb (115-160) 89 g/L Not done Not done Serum Creatinine (60-120) 403 mmol/L 58 77 Local data collection and analysis 100 consecutive patients with newly diagnosed myeloma who presented from July 2014 to July 2016 • Urine PCR and ACR, • Urine BJ positivity, • serum freelite levels • Presence or absence of renal impairment at diagnosis Results • Urine BJ negative in 29 patients – 100% had serum freelite <250 mg/L denoting reduced or negligible renal risk – 83% had normal Urine ACR and PCR and serum creatinine – 17% had abnormal creatnine due to unrelated causes and not due to myeloma • Urine BJ was positive in 66 patients – Urine PCR was done in 48 patients – Normal PCR in 12 patients denoted negligible urine light chains or bence jones s/o low renal risk due to myeloma – Urine PCR was abnormal i.e. >30 mg/mmol in 36 patients. – PCR was x10 ACR in 27 patients (27 patients) who also had relatively higher serum freelite value >1000mg/L and were at maximum renal risk. • In 14 patients urine ACR and PCR were available from before, Urine PCR was >30 and 2 x ACR value several months prior to diagnosis. • PCR was 10 x ACR in 8 of these patients suggested that myeloma could have been diagnosed many months earlier as shown in examples above. Follow up action after the study/audit • Biochemistry department will insert a comment “If PCR is raised i.e. >30 mg/mmol and > twice the value of ACR, please send a urine sample to immunology for Bence Jones (light chains) proteinuria” • GP newsletter was sent out in September 2016 emphasise the need to interpret the results of Urine PCR and ACR correctly and to request screening tests for myeloma i.e. urine Bence Jones protein early. • Earlier diagnosis of myeloma will eventually result in reduced rates of complications, reduced morbidity and improved overall survival • GP are understanding results of Urine ACR and PCR better and are asking for Urine BJ earlier. Other unusual ways of diagnosing myeloma • Panhypogammaglobulinaemia • Macrocytic anaemia – unexplained • Hyponatraemia (pseudo) • Hyperphosphatemia (pseudo) • High total protein but low albumin • Changes in Immunology lab – if a pp is detected automatically do serum freelites since Jan 2017 • Not to miss 15% of light chain myelomas CM 55 years old male • Na 131, Creat 140, • Ca 2.49 PO 4 2.70 (0.8-1.5) • alb 26 glb x • Hb 83 • Lymph 4.33, we missed plasmacytoid eclls in circulation in the lab • 3 weeks later GP asked for Igs as he suspected myeloma • IgG 90.2 IgA <0.25 IgM <0.15 • PP 69.6 Assessment of a patient - NG35 • Bloods: UE, LFT, Bone, CRP, FBC, • Immunoglobulins/SPE and Serum