Handout for lecture on plasma cell neoplasms presented by Rob McKenna

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1 Handout for lecture on plasma cell neoplasms presented by Rob McKenna The following slides represent a near final version of the presentation that will be given in Maui, January 23,2018. Minor changes in slides and order of slides may appear in the actual lecture. Issues In Plasma Cell Neoplasms Focus On WHO 2016 Presented by Rob McKenna Notice of Faculty Disclosure In accordance with ACCME guidelines, any individual in a position to influence and/or control the content of this CME activity has disclosed all relevant financial relationships within the past 12 months with commercial interests that provide products and/or services related to the content of this CME activity. The individual below have responded that they have no relevant financial relationship with commercial interest to disclose: Robert W. McKenna, MD 1

2 Plasma Cell Neoplasms (PCN) Traditional testing for plasma cell neoplasms Role of serum free light chain analysis, immunophenotyping and genetics Issues and new criteria in diagnosis of PCN Modified criteria for diagnosis of plasma cell myeloma Changes in the classification of MGUS Issues in diagnosis of solitary plasmacytoma Issues in diagnosis of amyloidosis Plasma cell neoplasms with a paraneoplastic syndrome WHO Classification 2016 Evaluation for Suspected Plasma Cell Neoplasm 2

3 Bone Marrow Aspiration Smears In Plasma Cell Myeloma IgA Plasma Cell Myeloma Convoluted Plasma Cell myeloma Plasmablastic Myeloma Cytoplasmic Crystalline Inclusions 3

4 Patterns of Marrow Involvement in PCM Interstitial Focal Diffuse Lambda Additional Assessment of PCN Serum free light chain analysis Immunophenotype Genetics Predictive factors (ISS for myeloma) Beta 2 microglobulin Serum Albumin Other Uses of Serum Free Light Chain Assay (Quantification and K/L ratio) Screening in combination with immunofixation electrophoresis Baseline values are prognostic MGUS Smoldering myeloma Symptomatic myeloma Plasmacytoma AL amyloidosis Hematologic responses to treatment AL amyloidosis; non secretory myeloma; Stringent complete response in plasma cell myeloma Dispenzieri, etal. International Myeloma Working Group guidelines for serum free light chain analysis in multiple myeloma and related disorders. Leukemia (2009) 23: Normal Kappa/Lambda Ratio: 0.26 to

5 Immunophenotyping Plasma Cell Neoplasms Immunohistochemistry Flow Cytometry Quantification of Plasma Cells in Plasma Cell Myeloma Kappa Identification of Clonal Plasma Cells Kappa Lambda 5

6 Differentiating Myeloma From Other Neoplasms CD138 Flow Cytometry Immunophenotyping of Plasma Cell Neoplasms Identification of clonal and aberrant plasma cells? Indicator of prognosis Detection of minimal residual disease (MRD) The Immunophenotype of Normal Plasma Cells (Histograms courtesy of Steve Kroft, MD) CD38 bright CD19(+) CD20( ) CD45(+) CD56( ) Polytypic Light Chains Normal Plasma Cells Normal B cells Granulocytes Monocytes 6

7 Flow Cytometry Histograms of Plasma Cell Myeloma Red = Myeloma plasma cells Blue = Normal B lymphocytes Immunophenotype of Plasma Cell Myeloma CD138+ CD20 (10-20% +) CD38+ CD56 (65-80% +) CD79a+ CD117 (30% +) Clonal CIg+ CD28 (16-48% +) CD200 (60-75% +) CD19 (5% +) Cyclin D1 -/+ CD45 (18-75% +) Sig -/+ CD27 (~50% +) CD52 -/+ CD81 (dim/- 95%) CD10 -/+ MRD Matters in Treated PCM Blood 2008;112:

8 Minimal Residual Myeloma (MRD) Day 100 Post Autologous Stem Cell Transplant Day 100 MRD s/p ASCT All patients (N=295) Paiva et al, Blood 2008: % of patients MRD positive, with median level of 0.14% (range.01 4%) Myeloma Cells Are Under Represented in Flow Cytometry Analyses 60 70% average decrement compared to aspirate differential count (Smock etal, Arch Pathol Lab Med 2007;131: ; Nadav etal, Br J Haematol 2006;133: ; Paiva, Haematologica 2009;94: ) Possible causes: Hemodilution Different distribution of plasma cells in particle associated and liquid marrow components than other cellular elements Loss in processing 8

9 Techniques in Genetic Analysis of Plasma Cell Neoplasms Conventional Karyotype Cytogenetics Fluorescent In Situ Hybridization (FISH) Gene Expression Profiling (GEP) Conventional Karyotype Cytogenetics Standard for detecting genomic abnormalities and outcome discrimination in plasma cell myeloma Only ~40% of PCM have identifiable abnormalities Deletion of 13 and hypodiploidy are prognostic karyotype changes These may not have FISHdefined risk abnormalities Karyotypes are courtesy of Michelle Dolan, MD, Univ. of MN, Cytogenetic Lab. Fluorescent In Situ Hybridization (FISH) >90% of cases have detectable abnormalities Cell sorting or cig FISH improves yield Employed for establishing risk based stratification Ahmann GJ, etal. Cancer Genet. Cytogenet 1998; 101: 7 Fonseca, R, etal. Cancer Res 2004; 64:1546 Avet Loiseau H, etal. Blood 2007; 109: 3489 Fonseca R, etal. Leukemia 2009; 23:2210 FGFR3 (4p16) /IGH (14q32) 5p15.2 / CEP9 / CEP15 FISH illustrations are courtesy of Michelle Dolan, MD, Univ. of MN Cytogenetics Lab. 9

10 Gene Expression Profiling (GEP) Powerful technique in patient stratification GEP signature distinguishes high and low risk myeloma Most sensitive and specific for identification of high risk PCM Use in clinical routine depends on some technical and logistical resolutions References Zhan F, etal. Blood 2006; 108:2020 (Molecular classification of PCN) Shaughnessy JS, etal. Blood 2007; 109:2276 (70 genes linked to high risk GEP70) Chng WJ, etal. Leukemia 2008; 22: 459 (Further validation of GEP70) Decaux O, etal. J Clin Oncol 2008; 26:4798 (15 gene model of risk) Broyl A, etal. Blood 2010; 116: 2543 Waheed S, etal. Cancer 2011; 117:1001 IMWG Molecular Cytogenetic Classification (Fonseca R, etal. Leukemia 2009; 23: 2210) Hyperdiploid (45%) Non hyperdiploid (40%) Cyclin D translocation 18% t(11;14)(q13;q32) 16% t(6;14)(p25;q32) 2% t(12;14)(p13;q32) <1% MMSET translocation 15% t(4;14)(p16;q32) MAF translocation 8% t(14;16)(q32;q23) 5% t(14;20)(q32;q11) 2% t(8;14)(q24;q32) 1% Unclassified (other) (15%) References Bergsagel PL and Kuehl WM. Oncogene 2001; 20: 5611 Fonseca R, etal. Blood 2003; 101: 4569 Keats JJ, etal. Blood 2003; 101:1520 Bergsagel P, etal. Blood 2005; 106: 296 Gertz MA, etal. Blood 2005; 106:2837 Carrasco DR, etal. Cancer Cell 2006; 313 Zhan F, etal. Blood 2006; 108:2020 Stewart AK, etal Leukemia 2007; 21:529 Avet Loiseau HA, etal. Blood 2007; 109: 3489 Shaughnessy JS, etal. Blood 2007; 109:2276 Chng WJ, etal. Leukemia; 2008; 22: 459 Decaux O, etal. J Clin Oncol 2008; 26: 4798 Avet Loiseau H, etal. Leukemia 2013; 27: 711 Mayo Stratification of Myeloma and Risk Adapted Therapy (msmart) Standard Risk (60%) Intermediate Risk (20%) t(11;14) t(4;14) t(6;14) Del 13 Hyperdiploid Hypodiploid All Others (OS=8 10yrs) (OS=4 5yrs) High Risk (20%) Del 17p t(14;16) t(14;20) GEP High Risk (OS=3yrs) Chesi M and Bergsagel PL. Int J Hematol 2013; 97:

11 WHO Classification of Plasma Cell Neoplasms (2008) Monoclonal gammopathy of undetermined significance (MGUS) Plasma Cell Myeloma Asymptomatic (Smoldering) Non secretory myeloma Plasma cell leukemia Plasmacytoma Solitary plasmacytoma of bone Extraosseous (extramedullary) plasmacytoma Immunoglobulin deposition diseases Primary amyloidosis Systemic Light and heavy chain deposition diseases POEMS syndrome (Osteosclerotic myeloma) WHO Criteria For Symptomatic Plasma Cell Myeloma (4th Edition 2008) M protein in serum or urine Bone marrow clonal plasma cells or plasmacytoma Related organ or tissue impairment (end organ damage) [Modified from International Myeloma Working Group. Br J Haematol 2003; ] Diagnostic Criteria for Plasma Cell Myeloma (Revised 4 th edition 2016) Clonal BM plasma cells > 10% or biopsy proven plasmacytoma and End organ damage attributable to the plasma cell proliferative disorder (CRAB) C: high calcium levels (>11 mg/dl) R: renal dysfunction (Cr >2 mg/dl) A: anemia (Hgb< 10 g/dl) B: bone destruction (CT or PET CT) or One or more specific biomarkers of malignancy 11

12 Biomarkers of Malignancy in PCM Clonal bone marrow plasma cells > 60% Involved:uninvolved serum free light chain ratio >100 >1 focal lesion on MRI studies Diagnostic Criteria for Smoldering (Asymptomatic) Myeloma Both criteria must be met: Serum M protein (IgG or IgA) >3.0g/dL or urinary M protein >500mg per 24 h and/or clonal bone marrow plasma cells 10 to 60% Absence of myeloma defining events (CRAB) or amyloidosis High Risk Smoldering Myeloma Dispenzeri A, etal. Blood 2013;122: year time to progression rates >60% o Extreme bone marrow plasmacytosis (>60%) o Extremely abnormal serum free light chain ratio (>100) o Multiple bone lesions detected only by MRI (>1 focal lesion) Dhodapkar MV, etal. Blood 2014; 123: 78 2 year time to progression rate 67% o Elevated SFLC, M spike, GEP70 risk score 12

13 High Risk Smoldering Myeloma Clinical trials have shown that asymptomatic myeloma patients with high risk features could benefit from treatment Delayed time to progression and improved overall survival Monoclonal Gammopathy of Undetermined Signif. (MGUS) MGUS is a potentially malignant clonal plasma cell expansion (precursor lesion) Defined by: M protein in serum < 3.0g/dl Marrow plasma cells < 10% and low level of infiltration in trephine biopsies No myeloma related end organ damage (CRAB) Monoclonal Gammopathy of Undetermined Signif. (MGUS) ~3% to 4% of persons >50 years of age A significant minority progress to a malignant plasma cell neoplasm Kappa Can not be certain at diagnosis which will remain stable Lambda 13

14 Risk of Progression in MGUS Risk of progression is about 1% per year and indefinite Size and type of M protein and serum free light chain ratio are most significant M protein of 25g/L >4 times risk of <5g/L IgM and IgA are at greater risk (~1.5%/yr.) Fraction of PC with an abnormal immunophenotype DNA aneuploidy Subnormal levels of polyclonal Ig Types of MGUS IgM MGUS (15%) Non IgM MGUS (85%) (70% IgG, 12% IgA) Differences Between IgM MGUS and Non IgM MGUS? Non IgM MGUS Plasma cell Genetics similar to myeloma Rate of progression is 1.0%/yr. IgM MGUS Lymphoplasmacytic MYD88 L265P mutation in ~50% of cases Rate of progression is 1.5%/yr. 14

15 Differences Between IgM MGUS and Non IgM MGUS Non IgM MGUS IgM MGUS Progression to plasma Progression to cell myeloma or primary lymphoplasmacytic amyloidosis lymphoma (WM) or other lymphoproliferative dis. WHO Recommendations on Segregating IgM and Non IgM MGUS Premise IgM MGUS is a distinct biologic and clinical entity whose only relationship to IgG and IgA MGUS is the presence of secreted M protein Recommendation Segregate the two types of MGUS IgM or Lymphoplasmacytic MGUS Non IgM or Plasma Cell MGUS (includes light chain MGUS) Definition of Light Chain MGUS Abnormal free light chain ratio (<0.26 or >1.65) Increased level of the involved free light chain No immunoglobulin heavy chain expression on IFE Urinary M protein <500mg/24hr; Clonal plasma cells <10% Absence of end organ damage (CRAB) or amyloidosis ( Up to 20% of MGUS; Rate of progression is 0.3%/year) 15

16 Criteria for diagnosis of PCN MGUS Smoldering Myeloma Plasma Cell Myeloma <3 g/dl M spike <10% plasma cells* 3 g/dl M spike OR 10% and <60% PCs* > 10% plasma cells* or plasmacytoma NO anemia, hypercalcemia, bony lesions, or renal dysfunction * in marrow Modified from Kyle RA et al. NEJM 2002;346(8): C: high calcium levels (>11 mg/dl) R: renal dysfunction (Cr >2 mg/dl) A: anemia (Hgb< 10 g/dl) B: bone destruction (usually lytic bone lesions) Or Biomarkers of malignancy Criteria for Diagnosis of Solitary Plasmacytoma Solitary lesion of bone or soft tissue consisting of clonal PCs Normal random BM biopsy without clonal PCs Normal skeletal survey and MRI or CT except for the solitary lesion Absence of end organ damage (CRAB) Criteria for diagnosis of solitary plasmacytoma with minimal bone marrow involvement: Same as above plus clonal PCs of <10% in random BM biopsy (60% vs. 10% progression in 3yrs.) Solitary Plasmacytoma of Bone 3% to 5% of PCN Spine is most common site (40% 50%) ~50% have M protein in serum or urine ~ 2/3 evolve to plasma cell myeloma Relatively indolent 16

17 High Risk Solitary Plasmacytoma of Bone Additional bone lesions identified only by MRI or PET/CT (~30% of cases) Significantly more likely to progress Considered plasma cell myeloma in new WHO Flow cytometry identification of occult disease 49% to 68% with clonal/aberrant plasma cells More likely to progress (70% vs 10%, med. 26 mo. vs NR) Presence of monoclonal urinary light chains More likely to progress (91% vs. 44%, med. 16 mo. vs 82 mo.) Extraosseous Plasmacytomas Lymph Node Most Common Primary Site ~ 80% in upper respiratory track (Spread to cervical nodes in~15%) Less Common Sites Lymph nodes (primary), salivary glands, thyroid, breast, GI track, CNS, etc. 20% have a low quantity M protein most IgA ~25% local recurrence, occasional spread to other sites ~15% progress to PCM Differential Diagnosis of Extraosseous Plasmacytoma Reactive plasma cell infiltrates Other lymphoid neoplasms that exhibit marked clonal plasma cell differentiation Marginal zone lymphoma Lymphoplasmacytic lymphoma Immunoblastic large cell lymphoma 17

18 Dual Immunostain for Kappa (brown) and Lambda (red) in Polytypic Plasma Cells Extraosseous Plasmacytoma vs. Lymphoma with Extreme Plasma Cell Differentiation Presence of areas in tissue section of typical lymphoma IgM monoclonal protein Detection of clonally related lymphocytes PC Immunophenotype by flow cytometry CD19( ), CD56(+) more likely plasmacytoma CD19(+), CD56( ) more likely lymphoma CD20(+) more likely lymphoma CD19(+) PCs: NHL 95% MM 5% Surface LC(+) PCs: NHL 76% MM 44% CD45: 91% v. 41% CD56: 33% v. 71% Abnormal B cell population NHL with plasmacytic differentiation Seegmiller et al, AJCP 2007;127: (Slide provided by Steve Kroft, MD) 18

19 Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome POEMS Syndrome TEMPI Syndrome POEMS Syndrome (Osteosclerotic Myeloma) Polyneuropathy Organomegaly Endocrinopathy M Protein Skin changes POEMS Syndrome (Osteosclerotic Myeloma) Paraneoplastic syndrome Osteosclerotic plasma cell neoplasm Low tumor burden with M protein at MGUS levels Genetic findings similar to other plasma cell neoplasms Symptoms related to products produced by the clonal plasma cells directly or indirectly, eg. VEGF Successful treatment is directed at PCN Lambda 19

20 Criteria for Diagnosis of POEMS Syndrome Mandatory Polyneuropathy Monoclonal plasma cell proliferative disorder Major (1 required) Castleman disease Osteosclerotic bone lesions VEGF elevation Minor (1 required) 6 criteria O, E, S, Papilledema, Thrombocytosis, Extravascular vol. overload Reticulin TEMPI Syndrome Telangiectasias Elevated EPO Erythrocytosis Monoclonal gammopathy Perinephric fluid collection Intrapulmonary shunting Schroyens W, etal. Complete and partial responses of the TEMPI syndrome to bortezomib. N Engl J Med 2012; 367: 778 TEMPI Syndrome 10 reported cases Appears to be a paraneoplastic syndrome Insidious onset M protein at MGUS levels Kappa light chain Low clonal plasma cells Lacking genetic studies Complete or partial response to bortezomib After Bortezomib 20

21 POEMS and TEMPI in WHO 2017 POEMS Syndrome Retain POEMS in its present status as a rare paraneoplastic syndrome associated with an osteosclerotic plasma cell neoplasm TEMPI Syndrome Include TEMPI as a provisional category in the classification of plasma cell neoplasms with a paraneoplastic syndrome Plasma Cell Neoplasms Associated with a Paraneoplastic Syndrome POEMS Syndrome (Osteosclerotic Myeloma) TEMPI Syndrome (Provisional) Revisions in the WHO Classification of Plasma Cell Neoplasms Monoclonal Gammopathy of Undetermined Significance Non IgM (Plasma cell) MGUS (Includes light chain MGUS) IgM (Lymphoplasmacytic) MGUS Plasma Cell Myeloma (New criteria) Molecular cytogenetic categories (IMWG) Clinical Variants Smoldering (asymptomatic) myeloma (High risk symptomatic myeloma) Non secretory myeloma Plasma cell leukemia Plasmacytoma (Changes in radiographic requirements) Solitary plasmacytoma of bone (SPB with minimal BM involvement) Extraosseous (extramedullary) plasmacytoma Immunoglobulin Deposition Diseases Primary amyloidosis (Definition, recommendations on amyloid testing) Systemic light and heavy chain deposition diseases Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome POEMS syndrome (Changes in criteria for diagnosis) TEMPI (Provisional) Thank you! Questions? 21

22 Immunoglobulin Deposition Diseases Primary amyloidosis Systemic light and heavy chain deposition diseases Characterized by visceral and soft tissue Ig deposition prior to development of a large tumor burden Leads to compromised organ function Primary (Light Chain) Amyloidosis (AL) ~90% have M protein, 70% lambda 72%serum 73% urine 7% >3 gm/dl M protein Median BM plasma cells 7% 20% of patients have myeloma t(11;14) present in > 40% of cases Diagnostic Criteria For Amyloidosis Tissue biopsy showing typical morphology Apple green birefringence under polarized light after Congo Red stain Typical fibrillar ultrastructure 22

23 Biopsy Diagnosis of Amyloidosis Bone marrow examination 56% Abdominal fat aspiration 80% Combined BM & fat aspirate 89% (Kyle and Gentry, Sem Hematol 32:55, 1995) Myocardial Biopsy Light Chain Amyloidosis PAS Congo Red 23

24 Issues in the Diagnosis of Primary Amyloidosis Light chain amyloidosis is associated with a clonal (neoplastic) plasma cell proliferation Essentially all cases of amyloidosis exhibit end organ damage End organ damage is caused by light chain amyloid deposition in tissues and organs Issues in the Diagnosis of Primary Amyloidosis Criteria for a diagnosis of plasma cell myeloma in patients with primary amyloidosis 10% or more plasma cells or an M protein at myeloma levels If plasma cell number and M protein are not at myeloma levels a diagnosis of myeloma should not be made 24