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Monoclonal Gammopathy Mahsa Mohebtash, MD Medical Director, Franklin Square Cancer Center at Loch Raven What Is Monoclonal Gammopathy?

Monoclonal Gammopathy Mahsa Mohebtash, MD Medical Director, Franklin Square Cancer Center at Loch Raven What Is Monoclonal Gammopathy?

Monoclonal Gammopathy Mahsa Mohebtash, MD Medical Director, Franklin Square Cancer Center at Loch Raven What is ?

• Monoclonal gammopathy or dyscrasia or paraproteinemia • Caused by proliferation of an abnormal clone of plasma cell or . • Includes a wide variety of clinical presentations/diseases. • Can be symptomatic or asymptomatic.

Monoclonal proteins

• An M protein is a monoclonal immunoglobulin secreted by a clone of plasma cells. • M protein can be an be an intact immunoglobulin (IgG, IgA, IgM, IgD) or can be composed of only light chains or only heavy chains. • M protein indicates an underlying clonal plasma cell or lymphoproliferative disorder.

• •≥10% plasma cells in the or biopsy-proven bony or • Plus one of the following: • End-organ damange (hypercalcemia, renal insufficiency, , lytic bone lesions) CRAB. • •A biomarker associated with near inevitable progression to end- organ damage: • ≥60% plasma cells in the bone marrow • Involved/uninvolved FLC ratio of 100 or more (involved FLC level must be at least 100 mg/L or more) • MRI with more than one focal lesion (involving bone or bone marrow) Smoldering Myeloma

• M protein ≥3 g/dL and/or 10 to 60 percent bone marrow plasma cells, plus: • No end-organ damage • Involved/uninvolved free light chain (FLC) ratio of < 100 • No MRI finding with more than one focal lesion (involving bone or bone marrow) Waldenstrom

• IgM monoclonal gammopathy in the + lymphoplasmacytic (LPL) in the bone marrow. • Symptoms: • Related to infiltration of tissues (anemia, lymphadenopathy, hepatosplenomegaly) • Effects of monoclonal IgM in the blood (hyperviscosity, ) • IgM multiple myeloma is extremely rare. Solitary Plasmacytoma

• Tumors composed of plasma cells • If solely in the bone, called “solitary plasmacytoma of bone” • If in soft tissues, called “solitary extramedullary plasmacytoma” • Four criteria must be met: • Biopsy-proven solitary lesion of the bone or soft tissue showing clonal plasma cells. • Normal bone marrow with no evidence of clonal plasma cells. • MRI or PET/CT is normal except for the primary solitary lesion. • Absence of lytic lesions, anemia, hypercalcemia, and renal insufficiency. • "solitary plasmacytoma with minimal marrow involvement" if clonal bone marrow plasma cells are <10 percent. Light chain (AL) Amyloidosis

• In AL amyloidosis (primary amyloidosis), monoclonal light chains that form fibrils which lead to organ dysfunction. • Congo red stain is positive. • <20% of marrow with plasma cells, no lytic bone lesions on imaging, and a modest amount of Bence Jones proteinuria. • Dx by biopsy of affected tissue, such as endomyocardium, abdominal fat, bone marrow, rectum, or kidney. • Rarely, MM can develop in patients with primary amyloidosis, usually in patients without cardiac or hepatic amyloid who live long enough to develop MM. • Conversely, the development of dipstick-positive proteinuria, hypoalbuminemia, and edema or in a patient with known MM suggests superimposed amyloidosis or light chain deposition disease. Light Chain Deposition Disease (LCDD)

• In light chain deposition disease, monoclonal light chains (typically kappa light chain) are deposited as granules (not fibrillar) in the tissues. Do not bind Congo red. • As with AL amyloidosis, LCDD may be associated with multiple myeloma or other conditions, such as lymphoma or Waldenström macroglobulinemia. • In the kidney, patients with predominant glomerular deposition may present with nephrotic syndrome (similar to AL amyloidosis), while those with predominant tubular deposition may present with renal insufficiency and relatively mild proteinuria. Heavy Chain Deposition Disease

• Rare B cell proliferative disorders • Production of an M protein consisting of a portion of the immunoglobulin heavy chain without a bound light chain. • Three types are recognized, based on the class of immunoglobulin heavy chain produced (eg, alpha, gamma, mu) • Dx by IHC of affected tissue (eg, mass lesion, lymph node, bone marrow) showing a clonal population of cells staining positively for a heavy chain but negative for both kappa and lambda light chains. POEMS Syndrome

• POEMS syndrome or osteosclerotic myeloma • Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes. • The cause of POEMS syndrome is unknown, although chronic overproduction of proinflammatory and other cytokines appears to be a major feature of this disorder. • Suspected in a patient with polyneuropathy and evidence for a monoclonal plasma cell disorder. • Peripheral neuropathy is required for the diagnosis, and usually dominates the clinical picture. • The diagnosis of POEMS syndrome requires the presence of both mandatory criteria (ie, polyneuropathy plus monoclonal plasma cell disorder), plus at least one major and one minor criterion. POEMS Dx Skin changes in POEMS syndrome

• Cryoglobulins are immunoglobulins (Ig) in the serum that precipitate at temperatures below 37°C and redissolve on rewarming. • : • Related to vascular occlusion by cryoprecipitate: • Digital ischemia • • Skin • • Constitutional Sx: • Fatigue • and myalgia • • Peripheral neuropathy Types of Cryoglobulinemia

• Type I: Cryoglobulins are monoclonal Ig, typically IgG or IgM, and less commonly IgA or free Ig light chains. • In the setting of monoclonal gammopathies (MGUS, MM, WM) or chronic lymphocytic (CLL). • Type II: Cryoglobulins are mixture of a monoclonal IgM (or IgG or IgA) with (RF) activity and polyclonal Ig. • In the setting of viral , particularly . • Other: virus, HIV, autoimmune diseases (mainly SLE and Sjögren’s), and lymphoproliferative disorders. • Type III: Cryoglobulins are mixture of polyclonal IgG and IgM. • In the setting of autoimmune disordes and sometimes HCV. MGUS (Monoclonal Gammopathy of Unknown Significance) • > 3 percent of the general population over the age of 50 and is typically detected as an incidental finding. • Asymptomatic premalignant clonal plasma cell or B cell proliferative disorder. • Defined by: • Serum monoclonal protein (M protein) <3 g/dL • bone marrow with <10 percent monoclonal plasma cells • absence of end-organ damage (lytic bone lesions, anemia, hypercalcemia, renal insufficiency, hyperviscosity, or CRAB). • A bone marrow evaluation may be deferred in patients with low-risk MGUS (IgG-type MGUS with serum M protein <1.5 g/dL, a normal serum FLC ratio), and with no bone pain or clinical concern for myeloma. Types of MGUS

• Most common subtype. Non-IgM MGUS • Can progress to smoldering or symptomatic myeloma. • Less often to AL amyloidosis or light chain deposition disease.

• ~ 15% of MGUS cases. IgM MGUS • Can progress to smoldering or symptomatic Waldenstrom macroglobulinemia. • Less often to AL amyloidosis or lymphoma.

• Secreted M protein lacks Ig heavy chain. Light chain MGUS • Can progress to smoldering or symptomatic light chain myeloma. • Or to AL amyloidosis or light chain deposition disease. Risks associated with MGUS

• Increased risk of peripheral neuropathy • associated with a higher risk of progression to AL amyloidosis. • Increased risk of fracture at 10 years (HR = 1.61), greatest for axial fractures. • The risk does not differ by (ie, IgG versus IgA) or M-protein concentration at diagnosis. • Fracture does not predict for disease progression to MM or Waldenström macroglobulinemia. • Recommend DXA scan and correction of vitamin D deficiency. • Increased risk of venous and arterial thrombosis. • Mechanism unclear, a hypercoagulable state secondary to an ongoing clonal plasma cell activity has been suggested. • Increased risk of . • Age-appropriate cancer screening programs for MGUS patients Management of MGUS • Progression to myeloma at 1% per year. • Rate may be slightly higher for IgM MGUS and slightly lower for light chain MGUS. • Median survival of patients with MGUS is only slightly shorter than that of age- matched controls. • No treatment is required for patients with MGUS • Annual (or biannual) SPEP, serum FLC assay, CBC, Cr, and serum calcium + H&P examination. • Risk of progression for low-risk non-IgM MGUS (serum M-protein <1.5 g/dL, IgG subtype, and normal serum FLC ratio) is only 5% over 20 years. When should we screen for monoclonal gammopathy? Unexplained Laboratory and Unexplained symptoms and Signs imaging findings • Peripheral neuropathy • Normochromic anemia • Pathologic fractures • High sed rate • Raynaud phenomenon, • Elevated serum viscosity • Elevated total protein • Hyperviscosity sx’s • Proteinuria • Heart failure • Hypercalcemia • Peripheral edema • Osteolytic lesions • Recurrent infections • Hypo- or hypergammoglobulinemia How should we screen for monoclonal gammopathy?

• Serum protein electrophoresis • Serum Screen • Serum light chains

• 24 hr urine protein electrophoresis and immunofixation • CBC, Creatinine, calcium Diagnosis • Immunoglobulins

• Bone marrow biopsy and aspirate • Bone imagings: skeletal survey, PET, MRI Work up • Echocardiogram, CMR Methods to detect M protein

• Serum protein electrophoresis (SPEP) Other Methods

• Immunofixation • Serum and urine free light chains • UPEP • Quantitative measures of immunoglobulins

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