Laboratories and the New IMWG Myeloma Guidelines

Transcription

1 Laboratories and the New IMWG Myeloma Guidelines David F. Keren, M.D. Professor of Pathology Division Director, Clinical Pathology The University of Michigan

2 Speaker Disclosure In the past 12 months, I have had no significant financial interest with the manufacturers that will be discussed in my presentation.

3 Objectives Attendees will be able to: incorporate new International Myeloma Working Group Guidelines into their laboratory practice implement a triage for detection of M- proteins appropriate for their clinical situation use the serum free light chain and heavylight chain analyses in their practice

4 What s happening to SMM? Pratt G et al. Brit J Haematol 2015 online 27 JUL 2015 DOI: /bjh November International Myeloma Working Group Guidelines (replaced 2003 Guidelines) Added alternatives to CRAB to establish MM! Hypercalcemia, renal impairment, anemia, bone disease Now includes highest risk asymptomatic patients Advanced Laboratory Testing Advanced Imaging Techniques

5 Tremor or Seismic Change? Debate about management of classic Smoldering Multiple Myeloma (SMM) Changes terminology Changes Design of future Clinical Trials Changes the role of laboratory biomarkers FLC Bone Marrow Plasma Cells Moves away from fatalistic outcome toward longer organ damage free survival and...

6 Categories of Monoclonal Gammopathies Katzmann, JA Clin Biochem Rev 30;105,2009 Plasma Cell Proliferative Disorders Multiple Myeloma (MM), plasmacytoma, plasma cell leukemia, Waldenström Macroglobulinemia Protein/Low Tumor Burden Diseases AL Amyloid, Light Chain Deposition Disease, POEMS (neuropathy) syndrome Premalignant: Monoclonal Gammopathy of Undetermined Significance (MGUS), Smoldering (Asymptomatic) Multiple Myeloma (SMM)

7 Multiple Myeloma Ludwig H, et al. Leukemia 2014;28: st disease with quantifiable tumor marker 2 nd most common cancer of the blood Annually, 120,000 new cases globally 10% of hematologic malignancies Median age 70 yr-but 2% under 40 yr Incidence varies by ethnicity and sex Chinese are Lowest 3.9/100,000 African are Highest 12.7/100,000 Men 2X> Women

8 Previous IMWG MM Definition IMWG Br J Haematol 2003;121:749 Bone Marrow Clonal Plasma cells >10% A Monoclonal Protein (serum or urine) except in true non-secretory MM (~2%) Evidence of end-organ damage related to the plasma cell proliferative process: CRAB HyperCalcemia Renal insufficiency Anemia Bone lesions (lytic or osteoporosis with compression fractures

9 Life Expectancy for MM Patients has Increased Prior to 1996 ~3 years 2012 Data: close to 8 years: New Therapies McCarthy et al. NEJM 2012;366:1770 Autologous Stem Cell Transplantation Thalidomide/Lenalidomide maintentance 85% in Stem Cell/Lenalidomide group alive at 3 years

10 Background Multiple Myeloma (MM) Cytogenetically heterogeneous 80% preceded by non-igm Monoclonal Gammopathy of Undetermined Significance (MGUS) 20% preceded by light chain MGUS IgM MGUS mainily evolves into Waldenström s, rarely MM

11 Previous IMWG of MGUS M-protein <3.0 G/dL IMWG Br J Haematol 2003;121:749 AND Bone Marrow <10% clonal plasma cells AND No symptoms attributable to the plasma cell process, i.e. Negative CRAB Prevalence increases with age 1 in 100 over 50yr, 1 in 20 over 70yr Not treated, ~1%/yr progress to malignancy

12 Does MGUS always precede Multiple Myeloma? Landgren et al. Blood 2009;113:5412. Nationwide prospective cancer study 77,469 healthy adults 71 developed Myeloma during study Serum samples yrs prior to MM Assayed serum for M-proteins Electrophoresis/Immunofixation Serum Free Light Chain test

13 MGUS Precedes MM by Years Yrs Prior to MM Landgren et al. Blood 2009;113:5412 N M-Spike rflc MGUS % 85.2% 100% % 79.3% 98.3% % 63.0% 97.9% % 67.6% 94.6% % 76.0% 100% % 73.3% 93.3% % 47.1% 82.4%

14 MGUS Risk Factors for Progression: Rajkumar et al Brit J Haematol 2005;106: Isotype Lower risk: IgG Higher risk IgA or IgM Size <1.5 G/dl lower risk Normal serum FLC ratio κ/λ lower risk

15 . MGUS Progression to MM Rajkumar et al Brit J Haematol 2005;106:

16 IMWG Recommendations for Following MGUS Kyle A et al. Leukemia 2015;24: Low Risk: one or no high risk factors Repeat SPEP in 6 months. If stable, follow every 2-3 years Intermediate/High Risk: 2 or 3 high risk factors Bone marrow aspirate and biopsy SPEP in 6 months and annually Any unexplained CRAB symptom: Bone Marrow including cytogenetics & FISH

17 First Report of Smoldering MM (SMM) Kyle RA and Greipp PR. NEJM 1980;302: patients with >10% plasmacytosis, >3g/L M- protein, but no end-organ damage Met laboratory criteria for MM Remained stable for 5 years without Rx Cumulative risk for MM was 73% in 15 years Intermediate Stage between MGUS and MM Various Names: Asymptomatic MM

18 Previous IMWG of SMM M-protein 3.0 G/dl IMWG Br J Haematol 2003;121:749 AND/OR Bone Marrow 10% clonal plasma cells AND No symptoms attributable to the plasma cell process, i.e. Negative CRAB Variable Risk of progression 10% Risk/yr progressing to MM or AL Amyloid 1 st 5 years 3% Risk/yr progressing in the next 5years 1% Risk/yr progressing in the next 10 years

19 SMM vs MGUS Progression Kyle RA et al. NEJM 2007;356:2586. Are these really treatable MM? Are these really MGUS with slightly higher M-protein? Smoldering Multiple Myeloma MGUS

20 SMM vs MGUS Rajkumar SV et al. Blood 2015;125: Biological Premalignancy (MGUSlike) CRAB Negative Biological Malignancy (lacking Myeloma- Defining Events: MDE)

21 Comparison of Older Definitions MGUS Symptoms: None BM Plasma cells: <10% And Serum M-protein: <3g/dL Rx: NONE SMM Symptoms: None BM Plasma cells: 10% And/Or Serum M-protein: 3g/dL Rx: NONE MM Symptoms: CRAB BM Plasma cells: 10% Serum M-protein: 3g/dL Rx:Chemo/Transpl

22 Signs & Symptoms that Prompt an Order for M-protein Studies for MM Calcium elevation Renal insufficiency, heavy proteinuria Anemia Bone disease back pain, osteopenia, osteolytic lesions, unexplained fractures Elevated serum protein &/or Sed Rate Frequent infections Peripheral neuropathy

23 Newly Detected M-proteins Brit J Haematol 2009;147:22-42 Site (n) Sweden (930) Italy (375) Mayo (1510) MGUS MM WM/LPD AL 72* * Percent of M-proteins detected

24 Older Definition of MM and Delay in Therapy Unlike other malignancies MM requires more than evidence of a clonal proliferation MM requires evidence of damage that may occur in several widespread organs: bone lesions, renal damage, anemia Older Therapy highly toxic Unable to identify individuals with precursor conditions likely to progress in a short period of time

25 Relationship of MGUS/SMM/MM Dispenzieri A et al. Blood 2013;26:4172. The vast majority of cases detected are MGUS They are found by serendipity a CRAB-like symptom that was unrelated to the plasma cell process A few cases are SMM, also detected by serendipity

26 What do we detect & Measure? Monoclonal Proteins (M-Proteins) Homogeneous immunoglobulin products from plasma cell clones Intact Immunoglobulin: IgG, IgA, IgM, IgD, IgE Free light chains: Kappa, Lambda Heavy Chains (gamma, mu & alpha) Suppression of normal immunoglobulins (Immunoparesis)

27 Excess Free light chains Antibody Production

28 Monoclonal Proteins in 1027 Newly Diagnosed Myeloma Kyle et. al., Mayo Clin Proc 2003

29 Methods: Serum Free Light Chain test & Electrophoresis Intact Molecules Serum Protein Electrophoresis Gel based techniques-immunofixation Capillary Electrophoresis-Immunosubtraction Nephelometry Total IgG, IgA or IgM Heavy/Light IgGK, IgGL, IgAK, IgAL, IgMK, IgML Free Light chains Urine Protein Electrophoresis-Immunofixation Serum Free Light Chain (FLC)

30 Immunoglobulin Structure A B C D S-S E F S-S S-S E F A B C D E F A B C D ~160 KDa in Serum too large to pass into urine ~25 KDa Free Light Chain Readily passes into urine

31 Serum FLC Ratio (rflc) Bradwell et al. Clin Chem 2001;47:673 Lambda (mg/l) Kappa LCMM Lambda LCMM Nonsecretory Myeloma AL Amyloidosis Normal Sera Renal Impairment Kappa (mg/l)

32 Mayo Study: FLC κ/λ at 100% Specificity, not 95% Katzmann et al. Clin Chem 2002;48:1437

33 If Urine is Not Sent, Serum rflc can Help Katzmann et al. Mayo Clin Proc 2006;81: Study: Serum FLC analysis on 428 patients with KNOWN urinary M-proteins by Immunofixation.

34 International Myeloma Working Group Suggested Uses of FLC Dispenzieri et al. Leukemia 2009;23: Serum FLC can substitute on screen for Urine Baseline measurement provides prognostic information for all plasma cell dyscrasias Detect & follow AL Amyloid*, LCDD and oligosecretory myeloma A criterion for Stringent Complete Remission NOT used to follow light chain myeloma NOT used when intact M-protein is followed in serum

35 62 y/o with lytic spinal lesions. Negative Serum IFE Oligosecretory Myeloma Urine IFE K L Bone Marrow- 70% plasma cells Serum Free κ = 0.27 mg/dl ( ) Serum Free λ = 5.09 mg/l ( ) Serum Free κ/λ =.053 ( )

36 Serum Protein Electrophoresis Levels of Resolution High Resolution Transferrin C3 Low Resolution

37 Endosmosis in Alkaline Gel (ph 8.6) Electrophoresis Ionic strength of positive buffer ions (+) determine flow to cathode Origin Anode + (+) (+) (+) (+) (+) (+) (+) Cathode

38 Capillary Electrophoresis Uses UV Light to detect Peptide Bonds 35 o C ph nm UV Detector Alb α-1 α-2 β-1 β-2 γ 25 µ diameter Fused silica capillary tube 20 cm long β Positive buffer ions (+) flow to cathode Cathode - Sample + Anode

39 Capillary Electropherogram Albumin haptoglobin α2 macroglobulin Transferrin Transthyretin α1 antitrypsin) C3 γ globulin

40 Monoclonal Gammopathy

41 Characterizing M-protein on gels: Apply Sample Immunofixation + + Electro Separation Apply Specific Antisera Wash and Stain SPE G A M K L

42

43 Urine Protein Electrophoresis

44 Densitometry & Immunofixation + albumin mg/24h mg/24hr

45 Immunosubtraction Pattern Tiselius & Kabat. J Exp Med 1939;69:

46 Albumin Immunosubtraction IgGK K moved from gamma region to albumin Serum G K G K M L G K G K A L G L G K M K A K anti-g anti-g anti-g anti-g G K A K G L K G K anti-g G K anti-g anti-g G K K G K G anti-g K G K G K G L A K L M L M K G A L

47 Large M-Spike ELP IgG IgA IgM K L

48 Large M-Spike IgG ELP IgG IgA IgM K K L

49 Initial Detection of M-Protein Serum Protein Electrophoresis & Free light M-protein Screen Suspicious + Neg Either* IFE on Urine or Serum FLC IFE or ISUB Neg Pos Pos Neg Report M-protein Negative Report Report M-protein + When M-protein-associated neuropathy is suspected IFE should be performed. *Both urine IFE and serum FLC should be performed if AL amyloidosis is suspected.

50 Sensitivity of M-Protein Screening Panels Katzmann et al. Clin Biochem Rev 30: , 2009

51 How do you measure an M-protein on SPEP samples? Do a total protein on the serum Identify the M-protein band Characterize it by Immunofixation or Immunotyping (Immunosubtraction) Create a densitometric scan (gel) or electropherogram (capillary electro) Perpendicular gate around the M-protein When M-spike <1/4-1/3 of the M-spike quantitation: Unable to quantitate

52 Perpendicular vs Tangent Schild et al. Clin Chem Lab Med 2008;46:876

53 Perpendicular 2.86 g/dl

54 Tangent 2.62 g/dl

55 Perpendicular Perpendicular 4.60 g/dl 4.41 g/dl 0.55 g/dl

56 Perpendicular Tangent 0.31 g/dl

57 Dilution Study Schild et al. Clin Chem Lab Med 2008;46:876 M-proteins serial 1:2 dilution in normal serum with12.3 g/l polyclonal IgG 50 g/l monoclonal IgG 25 g/l monoclonal IgA Peaks integrated by perpendicular drops or tangent skimming

58 Dilution Studies and Linearity Schild et al. Clin Chem Lab Med 2008;46:876 IMWG Minimal for measuring differences Recovery (%) Perpendicular linear to 15 g/l Tangent linear to 1.5 g/l (0.15 g/dl) Schild uses a 3.0 g/l as his lowest Zero Bias IgG & IgA Tangent Minimal Bias M-protein expected (g/l)

59 Tangent problem in beta or beta-gamma region

60 Beta region M-proteins: IMWG Recommends Total IgA to Follow Ludwig et. al. IMWG Guidelines, Leukemia : Interfering proteins Transferrin (beta1) C3 (beta 2) β-lipoprotein (on gels) Recommend: use total IgA by nephelometry

61 IgA Kappa

62

63 Dilution Study Total IgA vs Measured IgA IgA M-proteins serial 1:2 dilution in pooled normal serum with 220 mg/dl polyclonal IgA 1900 mg/dl monoclonal IgA Peaks integrated by using Immunotyping (Immunosubtraction) results as a guide

64 Patient Sample

65 IgA Sample 1 Neat g/dl

66 control

67 IgA Immunosubtraction IgA Electropherogram

68 IgA Immunosubtraction IgA Electropherogram

69 IgA Total vs IgA Measured Recovery (%) IgA Total (Nephelometry) Zero Bias M-protein measured M-protein expected (g/dl)

70 Quantitative Immunosubtraction (qis) Integration of Subtracted Area Lee Schroeder

71 Quantitative Immunosubtraction qis Correlation Plot qis Measured M-protein (g/dl)

72

73 Immunoglobulin Structure Shared Heavy-Light Unique Epitopes

74 Measures IgAK Separately from IgAL Bradwell AR et. al. Clin Chem 2009;55: IgAL (g/l) IgAK (g/l)

75 Katzmann Study Normal Range Katzmann et. al. Clin Chem 2015;61:360-7 For IgG and IgA HLC pairs 129 healthy serum donors (equally balanced for sex, ages 22-77) For rhlc reference interval Added 149 frozen samples without M- proteins from the Olmsted Study of Multiple Myeloma/MGUS

76 A 99% Confidence interval for Monitoring MM Katzmann et. al. Clin Chem 2015;61:360-7

77 IgG HLC Correlates with M-spike Katzmann et. al. Clin Chem 2015;61:360-7

78 IgG M-spike, HLC, IFE, Total IgG Katzmann et. al. Clin Chem 2015;61:360-7

79 IgA M-spike, HLC, IFE, Total IgA Katzmann et. al. Clin Chem 2015;61:360-7 In 7 pts, the initial samples had a symmetric beta fraction <2 G/dL & therefore did not have a quantifiable M-spike.

80 How do they Measure β M-proteins? Katzmann et. al. Clin Chem 2015;61:360-7 Low resolution SPEP doesn t separate beta1 from beta2 No measure if β was symmetric & <2g/dL As the M-protein... falls or rises around 2g/dL, the arbitrary gating of the M-spike is confusing for clinicians and patients. Although the M-protein is obscured, the IgA can still by quantified by Nephelometry

81 Lab Measurements & Rate of Progression to MM Concentration of M-protein Type of M-protein Serum rflc Bone Marrow Plasmacytosis Proportion of phenotypically clonal plasma cells Presence of Immunoparesis

82 SMM Progression & M-protein Kyle RA et al. NEJM 2007;356:2582 & Kyle RA et al. Lancet Haematol. 2014;1:e28. Serum M-protein size & mean time to progression 4g/dL 18 months <4g/dL 75 months Urine M-protein size- Percent in 5 years g/24hr 19% 1.0 g g/24hr 39%

83 SMM Progression & Immune Suppression Kyle RA et al. NEJM 2007;356:2582 & Time to progression: Nl uninvolved Ig 159 months of 1 uninvolved Ig 89 months of 2 uninvolved Ig 32 months

84 SMM Progression BMPC & M-protein Measurement Kyle RA et al. NEJM 2007;356:2586. BMPC 10% M-protein 3 g/dl BMPC 10% M-protein <3 g/dl BMPC <10% M-protein 3 g/dl

85 SMM Bone Marrow Plasmacytosis 60% Rajkumar SV et al. NEJM 2011;365: re-analysis of Mayo SMM study 2% of 276 pts had 60% BMPC >90% 2 yr progression & 5/6 progressed or died by 14 mo. Validated in new study 651 SMM pts 3% had 60% BMPC 95% progressed to MM within 2 yr. Conclusion: extreme plasmacytosis is rare in SMM because they usually have CRAB by then are are classified as MM

86 Considerations in 2011 Consensus Rajkumar SV et. al. NEJM 365:474-5, 2011 Very High-risk (VHR SMM) 40% progress/yr risk vs 10%/yr of most SMM few don t progress/3 yr vs 50% of most SMM How does this compare with cases formerly categorized as MM? 20% of VHR SMM don t progress in 2 yr similar to MM pts with minimal CRAB criteria Delay Rx- organ damage unacceptably severe Older Rx trials did not focus on high-risk

87 Serum free light chain in SMM Kastritis et al. Leukemia doi: /leu

88 Cytogenetic Alterations and SMM Progression Neben K et al. J Clin Oncol 2013;31:4325. t(4;14) del17p +1q Hyperdiploid High risk cytogenetics

89 Stratification of SMM Risk Dispenzieri A et al. Blood 2013;26:4172. Shaded 2 years BM>10% M >3g/dL BM>10% M>3g/dL rflc>8 FLC i/u >100 neg CD19 &/or neg CD45, over +56 Or wk38 & Suppress Nl igs MRI >1 lesion Presence Absence Bold del17p or t(4;14) solid only triomy dash other abn 17p,t(4;14, +1q21, or hyperdip & M>2g/dL bold both, sol lw FH >2 dsh hi FH<2 MGUS >1.5 g/dl rflc Non-IgG

90 Proposed Risk Evaluation for SMM Dispenzieri A et al. Blood 2013;26:4172.

91 High-Risk SMM: Rx with Lenalidomide + Dexamethasone Mateos et al. NEJM 2013; 369: Phase 3 study began 2009 Take advantage of new therapy and stratification of the highest risk group of SMM Smoldering MM: No CRAB symptoms Risk of progression to MM: 10%/yr Stratify based on High Risk findings

92 High-Risk Subgroup >50%/2yr BMP >10% & IgG M-protein 3 g/dl, or IgA 2 g/dl, or urine BJP> 1g/24 hr Or Either of above & Mateos et al. NEJM 2013; 369: % aberrant BMP & reductions in at least 1 of the uninvolved immunoglobulins, i.e. immunoparesis >25% compared to nl

93 Therapy Mateos et al. NEJM 2013; 369: Induction Therapy: Nine 4wk cycles 25 mg Lenalidomide (Revlimid) days wk rest 20 mg Dexamethasone days 1-4, Maintenance Therapy: 4 wk cycles initially until disease progression (see protocol amendment) 10 mg Lenalidomide (Revlimid) days 1-21, 1 wk rest 20 mg Dexamethasone days 1-4 only in asymptomatic biologic progression *Protocol Amendment: limit maintenance to 2 years

94 Safety of Protocol-Adverse Events 1 death pneumonia Mateos et al. NEJM 2013; 369:438-47

95 Freedom from Progression 3 yr Mateos et al. NEJM 2013; 369: % 30%

96 3 yr Survival Since Start of Study Mateos et al. NEJM 2013; 369: % 80%

97 Survival Since SMM Dx Mateos et al. NEJM 2013; 369:438-47

98 Myeloma Therapy Awaited Evidence of Organ Damage Rajkumar SV et al. Lancet 2014;15:e The requirement for end organ damage was okay when we had very limited options of treatment. But the myeloma working group decided it was not justifiable now. 1.Considerable advances in myeloma therapy 2. Major advances in laboratory testing and imaging-detect end organ damage before there was serious harm to patients 3. Accurate biomarkers allow us to define malignancy and need therapy before end organ damage is manifest

99 2014 IMWG Guidelines Rajkumar SV et al. Lancet 2014;15:e Reliable Biomarkers 80% probability of progression in 2 years Patients should be regarded as having MM Small SMM group- median time to development of end-organ damage was ~ 1 year Very high-risk cohort stood out from typical SMM Few disease free at 3 yr vs 50% of SMM free at 10 years Delay in offering therapy seemed unreasonable

100 Advantage of New IMWG Criteria Treatment of high-risk asymptomatic patients extends survival

101 New IMWG Guidelines Rajkumar SV et al. Lancet 2014;15:e In addition to end organ damage MM can be defined by any of the following: 1. BMPC of 60% or 2. rflc (involved/uninvolved) 100 or 3. MRI studies showing more than one focal lesion Treatable with no other evidence of damage Updated def of MGUS SMM & plasmacytoma Updated follow-up intervals for high-risk SMM

102 There Still are Borderline Issues For pts management and treatment There is still a lot of judgement in the area of attributable end organ damage Major implication: now we start therapy before end organ damage we can potentially improve quality of life and overall survival

103 New IMWG Definitions of: MGUS / SMM / MM Chesi M et al. Int J Lab Hematol 2015;37 (suppl. 1) Feature Non-IgM MGUS SMM MM BM Plasma cellls M-spike Myelomadefining event <10% AND <3 g/dl serum or <500 mg/d urine AND 10-60% OR 3 g/dl serum or 500 mg/d urine AND NONE NONE 1 j10% or bx proven plasmacytoma AND

104 Shrinking the Category of Smoldering MM Dispenzieri A Blood 2014;123:4-5

105 New IMWG MM definition Rajkumar SV et al. Lancet 2014;15:e Clonal BM plasma cells 10% or bx proven plasmacytoma And 1 or more Myeloma Defining Event

106 Myeloma Defining Events (any 1) Evidence of End Organ Damage (due to the plasma cell proliferation) CRAB: hypercalcemia or renal insufficiency or anemia or bone lesions or Clonal BM plasma cells 60% or Involved:Uninvolved serum free light 100 or >1 focal lesions on MRI studies

107 New SMM Definition Rajkumar SV et al. Lancet 2014;15:e Serum M-protein (IgG or IgA) 3g/dL or Urinary M-protein 500 mg/24h &/or Clonal BM plasma cells 10-60% & Absence of myeloma defining events or amyloidosis

108 High-Risk SMM-Not Treatment Ready Rajkumar SV et al. Blood 2015;125: * *Excludes patients without end-organ damage that NOW fall under MM: 60 clonal BMPC or ri/uflc 100 (plus measurable iflc 100 mg/l), or 0.1 focal lesion on MRI scan.

109 Details of Defining Events-Part I Plasma Cell related End Organ Damage Serum Ca >1mg/dL (>0.25 mmol/l) above upper limit of normal 11mg/dL (2.75 mmol/l) Cr Clearance <40 ml per min or Serum Cr>2mg/dL (177µmol/L) Hgb >2.0g/dL below the lower limit of normal or a Hgb <10.0g/dL 1osteolytic lesions on skeletal radiography (CT or PET-CT)

110 Details of Defining Events-Part II Biomarkers of Malignancy Clonal bone marrow plasma cell percentage 60% Involved:Uninvolved rflc 100 >1 focal lesions on MRI studies (each focal lesion 5 mm in size

111 Should we Screen for MGUS? Sigurdardottir EE et al. JAMAA Oncol 2015;1: All MM cases in Sweden ,798 cases of MM 392 MGUS that progressed to MM Calculated survival rates from the time of MM diagnosis Compare MM with MM-after MGUS

112 Better Survival of MM in Patients with prior MGUS Sigurdardottir EE et al. JAMA Oncol 2015;1:

113 ?An Association or More? Sigurdardottir EE et al. JAMA Oncol 2015;1:

114 Risks of Screening for MGUS Kyle RA & Rajkumar SV JAMA Oncol 2015;1: Mechanism of better survival unclear Were MGUS were followed more closely as a reason for better rx Maybe imply the dx was made earlier because of close follow-but the real time of survival is not different Prospective studies needed Cost, Inconvenience & Anxiety Probably override the possible potential benefit of screening for MGUS.

115 Probably Not Yet good enough Case for Screening but... IMWG has defined a stage of SMM that has NO SYMPTOMS as TREATABLE MM Mateos found better outcomes for highrisk SMM patients that have NO SYMPTOMS if they receive early Rx It seems the ONLY way to detect these TREATABLE individuals is to SCREEN an Asymptomatic Population Stay tuned...