Cancer Education Day Approach to Paraproteinemia or Why did I order that SPE?#! May 13, 2016 Dr Sindu Kanjeekal MD FRCPC Hematology and Medical Oncology

Disclosures No relevant disclosures

Objectives Epidemiology of MGUS Review of common tests Hypergammaglobulinemia vs MGUS Definition of MGUS, SMM, active MM Risk stratification of MGUS Special considerations for IgM MGUS

What are the most common reasons you order SPE? Evaluation of… Anemia Neuropathy reduced EGFR Proteinuria Connective tissue disease

Do you ever wish you hadn’t ordered that SPE? Yes No

Case #1 72 yo man. Lawyer. Phx: HTN, type II DM Presented with mild asymptomatic normocytic anemia for ~3 years. Jan 2014 Hb=111 Upper and lower endoscopy normal Jan 2016 Hb=117. (normal iron, B12/folate/TSH) Creat=122 SPE shows ill-defined band in gammaglobulin region IFE=IgG kappa protein

Case #1 Investigations Results Because of unexplained anemia, mild elevation of creatinine BM Biopsy SFLC ratio 24hr urine collection for protein and IFE Skeletal survey BMB-3% plasma cells SFLC ratio-normal 24hr urine normal Skeletal survey normal

1. What is this patient’s risk of progression to multiple myeloma at 20 years? B 5% C 20% D 60%

MGUS… Benign monoclonal proteins were first described by Dr. Jan Waldenström in 1960 after he detected abnormal narrow hypergammaglobulinemia bands in serum protein electrophoresis (SPEP) samples from healthy individuals SPEP often performed as a result of screening primary care for anemia nephrologists for renal insufficiency or proteinuria neurologists for peripheral neuropathy

Monoclonal Gammopathies Mayo Clinic 2011 Lymphoproliferative 1% (25) Amyloidosis (AL) 10% (174) SMM 5% (81) Solitary or extra- medullary 2% (34) Multiple myeloma 20% (348) Macro 3.5% (62) Other 7.5% (130) MGUS 51% (879)

What is MGUS? An asymptomatic plasma cell dyscrasia present in 3-5% of adults >50 yo Non IgM MGUS IgM MGUS Light chain MGUS Twice as common in African American population and more common in men than women Average risk of progression to MM=1%/year

Diagnostic Tests

Normal SPEP TBG haptoglobin CRP immunoglobulins transferrin

Abnormal SPEP Monoclonal protein

Serum Immunofixation

UPEP UPEP is used to detect Bence-Jones protein (BJP), which is a Kappa or Lambda light chain found dissociated from the regular Ig conformation The light chains are sufficiently small that they can be excreted by the kidneys once they reach a sufficient concentration in the blood. In 15% of multiple myeloma cases the only identifiable monoclonal product is BJP Ref: (Beetham et al., 2007; Merlini and Bellotti, 2003).

Serum Free Light Chain Assay

Other Conditions Associated with M-protein POEMS Rare paraneoplastic associated with plasma cell disorder (Lambda light chain) Rare skin disease Immune suppression- seen transiently post transplant Neurologic disorder sensorimotor peripheral neuropathy Renal Idiopathic focal glomerulonephrosclerosis hematologic Lymphoma/CLL Connective tissue disorders RA/SLE/PMR/AS

Most cases of MM are preceded by MGUS Why do we follow?

We want to avoid this…

Biological events related to progression to multiple myeloma. Biological events related to progression to multiple myeloma. The biologic transition from normal plasma cells to multiple myeloma precursor disease (monoclonal gammopathy of undetermined significance [MGUS] and smoldering myeloma) to multiple myeloma consists of many overlapping oncogenic events. These events do not all occur in each affected individual, for example, hyperdiploidy is present in approximately 50% of precursor and multiple myeloma tumors. In this illustration, solid lines approximate the period during which the oncogenic event is likely to occur; dashed lines indicate less certainty in the timing. Once an oncogenic event occurs, it almost always persists. The 2 major types of early events include IgH translocations [most commonly: t(4;14), t(14;16), t(6;14), t(11;14), and t(14;20)] and hyperdiploidy, although most tumor cells have only one of these two events. Either of these can coexist with deletion of chromosome 13, although this abnormality most commonly (> 80% to 90% of patients) occurs with the t(4;14), t(14;16), and t(14;20) IgH translocations.38,39 A unifying early event in most, perhaps all, precursor and multiple myeloma tumors is the dysregulation of a cyclin D gene. Secondary translocations, sometimes involving an Ig locus, can occur at any stage of myelomagenesis. Activating mutations of NRAS and KRAS are each present in about 15% of multiple myeloma tumors; NRAS mutations are present in MGUS tumors and KRAS mutations are absent from MGUS tumors. Constitutive activation of the nuclear factor κB (NFκB) pathway is mediated by mutations in some tumors during progression.38 Other events, such as Rb gene inactivation or deletion of p53 or p18 genes, are mostly seen at the level of advanced intramedullary or extramedullary multiple myeloma.38,65 Through the stage of intramedullary multiple myeloma, the tumor cells are strongly dependent on the bone marrow microenvironment.66 The reciprocal interaction of the bone marrow microenvironment and the tumor cells results in changes in the bone marrow microenvironment, which are responsible for the lytic lesions that are characteristic of multiple myeloma. Extramedullary tumor cells have developed features that make them independent of the bone marrow microenvironment. (Reprinted with permission.37)‏ Neha Korde et al. Blood 2011;117:5573-5581 ©2011 by American Society of Hematology

Definitions IMWG 2014 MGUS 1%/year SMM 10%/year Active MM Asymptomatic M-protein<30g/L Plasma cells<10% No CRAB criteria M-protein>=30g/L and/or Plasma cells>=10-60% No CRAB criteria or MDE (myeloma Defining Events) May or may not have symptoms M-protein in serum or urine And/or >=10% plasma cells and Presence of CRAB criteria or Myeloma defining events 60%>plasma cells SFLC ratio>100 2 or more focal lesions on MRI>=5mm (indicates focal BM abnormalities)

MGUS Prognostic Score Risk Factors Prognosis at 20 years M-protein >15g/L non IgG MGUS Abnormal SFLC ratio # Risk Factors Risk of progression at 20 years 5% 1 21% 2 37% 3 58%

Initial testing and follow-up

low risk MGUS (5% risk of progression at 20 years) Low risk MGUS (40% of MGUS) IgG subtype M-protein<15g/L normal SFLC ratio in the absence of concerning symptoms such as anemia or poor renal function no further initial evaluation is required

Low Risk MGUS At 6m follow with SPEP, CBC, Calcium, creatinine Or If stable then every 2-3 years Or Alternatively only if concerning symptoms arise

Intermediate and high risk MGUS (20-60% at 20 years) Consider Baseline BMB Bone imaging skeletal survey consider MRI (for high risk MGUS) because may show focal BM lesion which is a Myeloma Defining Event (MDE) Hx/Px, SPEP, CBC, Calcium, creatinine, q3-6m for 1st year then q6-12m

Case #2 Presentation Investigations 73 yo woman mild anemia and fatigue Past med Hx: osteoarthritis Presented in July 2013 after work-up for fatigue and back pain showed IgA M-protein BMB 7% atypical plasma cells. Normal cytogenetics Normal calcium, creatinine, skeletal survey SPE IgA 35g/L IgA kappa UPE IgA kappa SFLC ratio=3 (0.26-1.65)

Question #2 What is the diagnosis? Low risk MGUS High risk MGUS Smoldering Myeloma Active myeloma

Myeloma Smoldering MM~10%/year risk of progression Active MM M-protein>30g/L and/or 10-60% plasma cells No end organ damage or MDE Active MM Usually an M-protein Often >10% plasma cells but not necessary End organ damage CRAB Myeloma defining events SFLC ratio >100 >60% plasma cells 2 or more focal bone lesions on MRI

Probability of Progression SMM verus MGUS Figure 2. Probability of Progression to Active Multiple Myeloma or Primary Amyloidosis in Patients with Smoldering Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance (MGUS). I bars denote 95% confidence intervals. 1% per year vs 10% per year Kyle R et al. N Engl J Med 2007;356:2582-2590

SMM Prognostic Score Risk Factors Prognosis at 10 years >10% plasma cells M-protein >30g/L Abnormal SFLC Risk Factors Risk of progression at 10 years 1 50% 2 65% 3 84% In a retrospective review of 276pt at Mayo 1970-1995 Risk of progression to malignancy was 10%/year for the first 5 years Then 3%/year for next 5 years Then 1%/year thereafter

The case for observation… 50% of low risk SMM remain progression free after 5 years Only Alkylators and Steroids…until recently Hjorth M, Eur J Haematol 1993;50(2):95-102. Riccardi A, Br J Cancer 2000;82(7):1254-60.

Case #3 In 1999 a 62yo man presents with IgM MGUS Discharged from WRCC 2010 stable M-protein~15g/L In 2013 at age 73 diffuse adenopathy bilateral peripheral sensory neuropathy IgM ~17g/L LN biopsy-amyloid deposits BMB-lymphoplasmacytic lymphoma

IgM MGUS is associated with which of the following? Amyloidosis Waldenstrom’s Macroglobulinemia Isolated Peripheral neuropathy A and B All of the above

Special Case of IgM MGUS Association with neuropathy Neuropathy of IgM MGUS usually bilateral, peripheral sensory. EMG shows demyelinating pattern biopsy can show axonal loss Association with AL amyloid WM-IgM M-proten, lympadenopathy, hepatosplenomegaly, BMB plasmacytoid lymphocytes, hyperviscocity IgM Myeloma very rarely

IgM M-protein

Summary

For Low risk MGUS, what is this risk of progression to multiple myeloma at 20 years? B 5% C 20% D 60%

Low risk MGUS High risk MGUS Smoldering Myeloma Active myeloma If pt presents with M-protein=35g/L, BMB=7% plasma cells, no end organ damage. What is the diagnosis? Low risk MGUS High risk MGUS Smoldering Myeloma Active myeloma

IgM MGUS is associated with which of the following? Amyloidosis Waldenstrom’s Macroglobulinemia Isolated Peripheral neuropathy A and B All of the above

Summary Low Risk MGUS Intermediate and High risk MGUS Smoldering MM risk of progression 5% at 20 years do not need BMB short follow-up to ensure stable Intermediate and High risk MGUS consider BMB, bone imaging, MM labs Ongoing follow-up q6m then annually Smoldering MM need careful ongoing follow-up q6m but at 5 years 50% will not progress IgM MGUS needs special attention

Useful References September-october 2014, vol 11. Issue 5. www.hematology.org. Ask the Hematologist. A diagnostic Approach to Patients with IgM monoclonal protein Blood Reviews 23 (2009) 257-265. S Madan and P Greipp. Review:The incidental monoclonal protein: Current approach to management of MGUS Lancet Oncology. Nov 2014. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma

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