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Multiple Myeloma and Related Disorders Multiple Myeloma and The M protein in PCDs can be detected by serum or urine protein electrophoresis (SPEP and UPEP), but isolated light Related Disorders chains (r or ),) might be missed on protein electrophoresis. SPEP and UPEP are good initial screening tests to identify and Overview quantify the presence of an M spike, and the serum FLC assay B cell maturation to plasma cells involves antigen independent is a sensitive test to identi[z and quantify FLCs not bound to and antigen dependent phases. When humoral immunilr is hear,y chains in the serum. Neither SPEP nor UPEP can iden- stimulated (infection or inflammation), multiple clones of tily the subtype of immunoglobulin in the M spike, and both plasma cells are expanded and produce immunoglobulins of may miss small IM proteins. Semm and urine immunoflxation different classes and specificity, giving the polyclonal spike are more sensitive tests that can subtype the immunoglobulin. seen on protein electrophoresis. In contrast, plasma cell dys- SPEP helps differentiate a monoclonal spike from a po$clonal crasias (PCDs) or monoclonal gammopathies are a clonal spike, which are commonly seen with infections (e.g., hepati- expansion of the plasma cell or lymphoplasmacytic cell, tis C virus, HIV), inflammatory processes, and chronic liver which produces a uniform monoclonal spike (M spike) on disease and do not usually require further hematologic evalu protein electrophoresis. This monoclonal (M) protein can be ation. In inflammatory and inf'ectious processes, r and )" FLCs a complete immunoglobulin, with a heavy chain (lgG, IgA, are increased, but proportionately, so the ratio remains nor IgD, or IgM) complexed with a light chain (rc or )"), or free mal. Patients with a PCD secrete one type of FLC, leading to an Iight chains (FLCs) without a heavy chain component. increase in the involved light chain and an abnormal FLC ratio. Various PCDs have been described (Table 6). Note that an M Although monoclonal gammopathy of undetermined spike denotes the presence of M protein, whereas IgM is significance (MGUS) and multiple myeloma (1t4M) are common immunoglobulin M. causes ofabnormal M proteins, other disorders can also pro duce an M spike (see Table 6), and patients should be evaluated for the signs and symptoms of these diseases (see Table 7). Evaluation for Monoclonal Tests considered during the evaluation of monoclonal gam- Gammopathies mopathies include complete blood count with differential; serum chemistries, including creatinine, calcium, and albu Evaluation for monoclonal gammopathies is typically min levels; p, microglobulin; SPEP; UPEP; serum and urine restricted to patients with signs and symptoms, although a immunofixationi serum FLC tests; and quantitative immuno monoclonal gammopathy may also be identified incidentally globulins. Historically, plain radiographs ofthe bones (skeletal with an elevated serum protein level on blood tests or during surveys) were used to determine the presence of lytic lesions evaluation ofneuropathy, vasculitis, or kidney injury (Table z). in patients with MM. Bone scans, which detect increased osteoblast activity in most bone metastases, do not detect the purely lytic lesions in MM and are not useful. Commonly, PET TABLE 6. Disorders Associated With Monoclonal Gammopathies scans and MRI are used to detect l1'tic bone lesions. Bone marrow aspirate and biopsy quantify the percentage Plasma Cell Disorders of plasma cells in the marrow and help classify the PCD. Monoclonal gammopathy of undetermined significance" Cytogenetic evaluation of the bone marrow aspirate is impor Multiple myeloma tant for prognosis. Bone marrow testing can be deferred in lmmunoglobulin light-chain (AL) amyloidosis patients with low risk features, such as an IgG gammopathy Monoclonal immunoglobulin deposition disease measuring less than 1.5 g/dl, a normal serum FLC ratio, and Proximaltubulopathy (with or without Fanconi syndrome); no evidence of end organ damage. monoclonal gammopathy of renal significance Solitary extramedullary or bone plasmacytoma POEMS synd rome/osteosclerotic myeloma . Tests necessary for the evaluation of monoclonal gam- mopathies include complete blood count with differen B-Cell Disorders tial, serum chemistries, B2-microglobulin, serum and Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma urine protein electrophoresis, serum and urine immuno Marginal zone lymphoma fixation, serum free light chain testing, and quantitative Chronic lymphocytic leukemia/small lymphocytic lymphoma immunoglobulins. Heavy chain disease . Bone marrow evaluation need not be undertaken in HVC

Multiple Myeloma and The M protein in PCDs can be detected by serum or urine protein electrophoresis (SPEP and UPEP), but isolated light Related Disorders chains (r or ),) might be missed on protein electrophoresis. SPEP and UPEP are good initial screening tests to identify and Overview quantify the presence of an M spike, and the serum FLC assay B cell maturation to plasma cells involves antigen independent is a sensitive test to identi[z and quantify FLCs not bound to and antigen dependent phases. When humoral immunilr is hear,y chains in the serum. Neither SPEP nor UPEP can iden- stimulated (infection or inflammation), multiple clones of tily the subtype of immunoglobulin in the M spike, and both plasma cells are expanded and produce immunoglobulins of may miss small IM proteins. Semm and urine immunoflxation different classes and specificity, giving the polyclonal spike are more sensitive tests that can subtype the immunoglobulin. seen on protein electrophoresis. In contrast, plasma cell dys- SPEP helps differentiate a monoclonal spike from a po$clonal crasias (PCDs) or monoclonal gammopathies are a clonal spike, which are commonly seen with infections (e.g., hepati- expansion of the plasma cell or lymphoplasmacytic cell, tis C virus, HIV), inflammatory processes, and chronic liver which produces a uniform monoclonal spike (M spike) on disease and do not usually require further hematologic evalu protein electrophoresis. This monoclonal (M) protein can be ation. In inflammatory and inf'ectious processes, r and )" FLCs a complete immunoglobulin, with a heavy chain (lgG, IgA, are increased, but proportionately, so the ratio remains nor IgD, or IgM) complexed with a light chain (rc or )"), or free mal. Patients with a PCD secrete one type of FLC, leading to an Iight chains (FLCs) without a heavy chain component. increase in the involved light chain and an abnormal FLC ratio. Various PCDs have been described (Table 6). Note that an M Although monoclonal gammopathy of undetermined spike denotes the presence of M protein, whereas IgM is significance (MGUS) and multiple myeloma (1t4M) are common immunoglobulin M. causes ofabnormal M proteins, other disorders can also pro duce an M spike (see Table 6), and patients should be evaluated for the signs and symptoms of these diseases (see Table 7). Evaluation for Monoclonal Tests considered during the evaluation of monoclonal gam- Gammopathies mopathies include complete blood count with differential; serum chemistries, including creatinine, calcium, and albu Evaluation for monoclonal gammopathies is typically min levels; p, microglobulin; SPEP; UPEP; serum and urine restricted to patients with signs and symptoms, although a immunofixationi serum FLC tests; and quantitative immuno monoclonal gammopathy may also be identified incidentally globulins. Historically, plain radiographs ofthe bones (skeletal with an elevated serum protein level on blood tests or during surveys) were used to determine the presence of lytic lesions evaluation ofneuropathy, vasculitis, or kidney injury (Table z). in patients with MM. Bone scans, which detect increased osteoblast activity in most bone metastases, do not detect the purely lytic lesions in MM and are not useful. Commonly, PET TABLE 6. Disorders Associated With Monoclonal Gammopathies scans and MRI are used to detect l1'tic bone lesions. Bone marrow aspirate and biopsy quantify the percentage Plasma Cell Disorders of plasma cells in the marrow and help classify the PCD. Monoclonal gammopathy of undetermined significance" Cytogenetic evaluation of the bone marrow aspirate is impor Multiple myeloma tant for prognosis. Bone marrow testing can be deferred in lmmunoglobulin light-chain (AL) amyloidosis patients with low risk features, such as an IgG gammopathy Monoclonal immunoglobulin deposition disease measuring less than 1.5 g/dl, a normal serum FLC ratio, and Proximaltubulopathy (with or without Fanconi syndrome); no evidence of end organ damage. monoclonal gammopathy of renal significance Solitary extramedullary or bone plasmacytoma POEMS synd rome/osteosclerotic myeloma . Tests necessary for the evaluation of monoclonal gam- mopathies include complete blood count with differen B-Cell Disorders tial, serum chemistries, B2-microglobulin, serum and Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma urine protein electrophoresis, serum and urine immuno Marginal zone lymphoma fixation, serum free light chain testing, and quantitative Chronic lymphocytic leukemia/small lymphocytic lymphoma immunoglobulins. Heavy chain disease . Bone marrow evaluation need not be undertaken in HVC POEJ\y'S = polyneuropathy, organomegaly, endocrinopathy, presence of M protein, patients with a monoclonal gammopathy and low-risk and skin changes. feafures, such as an IgG gammopathy less than 1.5 g/dl, uMany diseases may be associated with monoclonal gammopathy of undetermined normal serum free light chain ratio, and no end organ significance, including but not limited to connective tissue diseases, hepatitis C, HIV cryoglobulinemla, and cold agglutinin disease. damage.

POEJ\y'S = polyneuropathy, organomegaly, endocrinopathy, presence of M protein, patients with a monoclonal gammopathy and low-risk and skin changes. feafures, such as an IgG gammopathy less than 1.5 g/dl, uMany diseases may be associated with monoclonal gammopathy of undetermined normal serum free light chain ratio, and no end organ significance, including but not limited to connective tissue diseases, hepatitis C, HIV cryoglobulinemla, and cold agglutinin disease. damage. 12

Multiple Myeloma and Related Disorders TABLE 7. Common Clinical Scenarios for Consideration of Plasma Cell Dyscrasia Testing" Clinical Scenario Disease Considerations Disease Characteristics Additional lnvestigative Evaluationb Lytic bone lesions or MM Osteolytic bone lesions, PTH- None hypercalcemia independent hypercalcemia Age-ina ppro priate MGUS, MM Osteopenia or osteoporosis with None bone loss' or without associated fractu res

Lytic bone lesions or MM Osteolytic bone lesions, PTH- None hypercalcemia independent hypercalcemia Age-ina ppro priate MGUS, MM Osteopenia or osteoporosis with None bone loss' or without associated fractu res Peripheral neuropathy AL amyloidosis; MM, WM (rare), Sensorimotor axonal Tissue aspirate/biopsy for MGUS polyneuropathy amyloid POEMS syndrome; MGUS, MM, Sensorimotor infl ammatory VEGF measurement, endocrine solitary plasmacytoma of bone demyelinating polyneuropathy, evaluation hepatosplenomegaly, endocrinopathies (hypogonadism, adrenal insufficiency), hyperpigmentation, hypertrichosis, m u lticentric Castleman disease, osteosclerotic bone lesions Cryoglobulinemic vasculitis; Sensory or sensorimotor Cryoglobulins, complement MGUS, MM, B-cell non-Hodgkin polyneuropathy, levels, hepatitis evaluation lymphoma (e.g.,WM) mononeuropathy multiplex Kidney disease Cast nephropathy; MM Acute kidney injury, nonalbumin Kidney biopsy proteinuria (monoclonal FLCs), bland urine sediment AL amyloidosis; MGUS, MM Nephrotic syndrome Tissue aspirate/biopsy for amyloid Monoclonal gammopathy of Varied kidney manifestations in Kidney biopsy renal significance patients who otherwise meet criteria for MGUS with a small plasma clone Proximal tubulopathy +/- Fanconr Normal anion gap, hyperchloremic Kidney biopsy, serum syndrome metabolic acidosis (proximal RTA), phosphorus and uric acid, hypophosphatemia, hypouricemia, urinalysis renal glucosuria, amino aciduria

Peripheral neuropathy AL amyloidosis; MM, WM (rare), Sensorimotor axonal Tissue aspirate/biopsy for MGUS polyneuropathy amyloid POEMS syndrome; MGUS, MM, Sensorimotor infl ammatory VEGF measurement, endocrine solitary plasmacytoma of bone demyelinating polyneuropathy, evaluation hepatosplenomegaly, endocrinopathies (hypogonadism, adrenal insufficiency), hyperpigmentation, hypertrichosis, m u lticentric Castleman disease, osteosclerotic bone lesions Cryoglobulinemic vasculitis; Sensory or sensorimotor Cryoglobulins, complement MGUS, MM, B-cell non-Hodgkin polyneuropathy, levels, hepatitis evaluation lymphoma (e.g.,WM) mononeuropathy multiplex Kidney disease Cast nephropathy; MM Acute kidney injury, nonalbumin Kidney biopsy proteinuria (monoclonal FLCs), bland urine sediment AL amyloidosis; MGUS, MM Nephrotic syndrome Tissue aspirate/biopsy for amyloid Monoclonal gammopathy of Varied kidney manifestations in Kidney biopsy renal significance patients who otherwise meet criteria for MGUS with a small plasma clone Proximal tubulopathy +/- Fanconr Normal anion gap, hyperchloremic Kidney biopsy, serum syndrome metabolic acidosis (proximal RTA), phosphorus and uric acid, hypophosphatemia, hypouricemia, urinalysis renal glucosuria, amino aciduria Cryoglobulinemic vasculitis Membranoproliferative Cryoglobulins, complement glomerulonephritis with levels, hepatitis evaluation proteinuria and active urinary sediment Ane mt MM Normocytic (occasiona ly I None macrocytic) anemia

Cryoglobulinemic vasculitis Membranoproliferative Cryoglobulins, complement glomerulonephritis with levels, hepatitis evaluation proteinuria and active urinary sediment Ane mt MM Normocytic (occasiona ly I None macrocytic) anemia AL amyloidosis = immunoglobulin light-chain amyloidosis; FLC = free light chain; MGUS = monoclonal gammopathy of undetermined significance; Mlvl = multiple myeloma; POEI\,'1S = polyneuropathy, organomegaly, endocrinopathy, M proteln, and skin changes; PTH = parathyroid hormone; RTA = renal tubular acidosis; VEGF = vascular endothelial growth factor; WM = Waldenstrom macroglobulinemia. 'This is not an all-inclusive list; other less common conditions can be associated with plasma cell dyscrasias. t'Evaluation beyond the standard evaluation for a monoclonal gammopathy. 'Premenopausal women or men <65 years of age with no additional risk factors for bone loss.

AL amyloidosis = immunoglobulin light-chain amyloidosis; FLC = free light chain; MGUS = monoclonal gammopathy of undetermined significance; Mlvl = multiple myeloma; POEI\,'1S = polyneuropathy, organomegaly, endocrinopathy, M proteln, and skin changes; PTH = parathyroid hormone; RTA = renal tubular acidosis; VEGF = vascular endothelial growth factor; WM = Waldenstrom macroglobulinemia. 'This is not an all-inclusive list; other less common conditions can be associated with plasma cell dyscrasias. t'Evaluation beyond the standard evaluation for a monoclonal gammopathy. 'Premenopausal women or men <65 years of age with no additional risk factors for bone loss. has a high prevalence rate and low risk ofprogression to symp- Monoclonal Gammopathy of tomatic disease, it is important to provide an accurate prognosis U ndetermined Sig nificance and appropriate counseling and management. The three types MGUS is characterized by an M protein Ievel less than 3 g/dl of MGUS, based on tlpe of M protein, are non-IgM, IgM, and (or less than 500 mg/24 h of urinary monoclonal FLCs), clonal light chain. NonJgM MGUS can progress to MM and, although plasma cells comprising less than 10'7. of the bone marrow less likely, to other PCDs at a rate of 1% per year. IgM MGUS has cellularity, and the absence of related signs and symptoms of the potential to progress to Waldenstrom macroglobulinemia at end-organ damage (Table 8). a rate of1.5% per year. Light-chain MGUS can progress to other The prevalence of MGUS increases with age, occuring in PCDs at a rate of 0.3%. In addition to the type of M protein, fac- approximately 3% of persons older than 50 years and 5'1, of tors that predict the risk of progression include the quantity of persons older than 70 years. When an asymptomatic condition M protein and an abnormal serum FLC ratio (Table 9). 13

Multiple Myeloma and Related Disorders TABLE 8 Diagnostic Criteria for the Plasma and Lymphoplasmacytic Cell Dyscrasias Diagnosis M Protein Bone Marrow Clonal Plasma Cells Disease-Specific or Lymphoid Cells Signs/Symptoms MG US Non-lgM (lgG, lgA) <3 g/dL <10"/" No lgM <3 g/dL <10"/o No Light chain" Affected serum FLC increased and <10"/" No serum FLC ratio increased Urinary M protein <500 mg/24 h Smoldering myelomab lgG or lgA >3 g/dL or r or ). urinary 10o/"'59"/" No FLC M protein >500 mg/24 h Smoldering WMb lgM >3 g/dL >10% No Multiple myeloma requiring Present (absent in nonsecretory >10o/o or biopsy evidence of a bony or Yes therapy disease) extramedu lary plasmacytoma I WM requiring therapy Present >-10"/" Yes CRAB Criteria for Myeloma-Related Signs and Symptoms HyperCalcemia:Serumcalcium>1 1mg/dL(2.Bmmol/L) or>1 mg/dL(0.3mmol/L) higherthantheupperlimitof normal Renal failure: Serum creatinin e>2 mg/dL(17 7 pmol/L) or creatinine clearance <40 mUmin

WM requiring therapy Present >-10"/" Yes CRAB Criteria for Myeloma-Related Signs and Symptoms HyperCalcemia:Serumcalcium>1 1mg/dL(2.Bmmol/L) or>1 mg/dL(0.3mmol/L) higherthantheupperlimitof normal Renal failure: Serum creatinin e>2 mg/dL(17 7 pmol/L) or creatinine clearance <40 mUmin Anemia: Hemoglobin<109/dL(100 g/Llor2g/dL(20 g/L) belowthe lowerlimitof normal Bone disease: >1 lytic bone lesions on imaging studies SLIM Criteria for Myeloma-Defining Biomarkers >60% clonal plasma cells on bone marrow examination (Sixty) lnvolved/uninvolved serum FLC ratio >1 00'(Llght chains) >1 focal lesion on MRI (MRl) WM-Related Signs and Symptoms Systemic symptoms: Fatigue, B symptoms (fevers, night sweats, weight loss), neuropathy, hyperviscosity Physical examination findings: Symptomatic lymphadenopathy or hepatosplenomegaly I Laboratoryfindings: Cytopenias (anemia, thrombocytopenia) FLC = free light chain; MGUS = monoclonal ga mmopathy of undetermined significance; WM = Waldenstrom macroglobulinemia. alight chain MGUS does not have a heavy chain component. bSmoldering myeloma or WM may have the diagnostic lV protein level with or without the percentage of bone marrow clonal p asma or lymphoid ce ls. 'lnvolved light chain must be greater than 1 00 mg/L. Data from Rajkumar SV, Dimopoulos MA, Palumbo A, et al. lnternational Myeloma Working Group updated criteria for the d iag nosis of mu ltiple mye oma. Lancet Oncoi. 2014;1 5 e538 48. IPMID: 25439696] doi:10.1 016/51470 2045(14)7A442 5

alight chain MGUS does not have a heavy chain component. bSmoldering myeloma or WM may have the diagnostic lV protein level with or without the percentage of bone marrow clonal p asma or lymphoid ce ls. 'lnvolved light chain must be greater than 1 00 mg/L. Data from Rajkumar SV, Dimopoulos MA, Palumbo A, et al. lnternational Myeloma Working Group updated criteria for the d iag nosis of mu ltiple mye oma. Lancet Oncoi. 2014;1 5 e538 48. IPMID: 25439696] doi:10.1 016/51470 2045(14)7A442 5 Patients with MGUS are also at higher risk of osteoporosis (e.g., diabetes or hypertension), these patients should be diag and fracture of the axial skeleton, and bone mineral density nosed with monoclonal gammopathy of renal significance, testing should be considered. Patients also have shorter sur which requires myeloma like therapy to prevent progressive vival than matched controls. and irreversible kidney injury. Treatment is not required. Patients commonly undergo follow up for sigrrs and symptoms of progression, initially at XEY PO I ]IIt 6 months and then yearly, if stable. Patients with low-risk MGUS o Monoclonal gammopathy of undetermined significance can be clinically observed and do not require follow-up testing. is characterized by an M protein level less than 3 g/dl, Kidney disease in patients with monoclonal gammopathy clonal plasma cells comprising less than 10'1, of the bone has traditionally been linked to light chain nephrotoxicity in marrow cellularity, and the absence of related signs and those with MM or amyloid infiltration in those with amyloido- symptoms of end organ damage. sis. More recent data suggest that some patients with features o Patients diagnosed with monoclonal gammopathy of otherwise consistent with MGUS may, nonetheless, have sig- renal significance require myeloma-like therapy to pre- nificant kidney disease related to the abnormal immunoglob vent progressive and irreversible kidney injury. ulin. If other, more likely causes of kidney injury are excluded

Patients with MGUS are also at higher risk of osteoporosis (e.g., diabetes or hypertension), these patients should be diag and fracture of the axial skeleton, and bone mineral density nosed with monoclonal gammopathy of renal significance, testing should be considered. Patients also have shorter sur which requires myeloma like therapy to prevent progressive vival than matched controls. and irreversible kidney injury. Treatment is not required. Patients commonly undergo follow up for sigrrs and symptoms of progression, initially at XEY PO I ]IIt 6 months and then yearly, if stable. Patients with low-risk MGUS o Monoclonal gammopathy of undetermined significance can be clinically observed and do not require follow-up testing. is characterized by an M protein level less than 3 g/dl, Kidney disease in patients with monoclonal gammopathy clonal plasma cells comprising less than 10'1, of the bone has traditionally been linked to light chain nephrotoxicity in marrow cellularity, and the absence of related signs and those with MM or amyloid infiltration in those with amyloido- symptoms of end organ damage. sis. More recent data suggest that some patients with features o Patients diagnosed with monoclonal gammopathy of otherwise consistent with MGUS may, nonetheless, have sig- renal significance require myeloma-like therapy to pre- nificant kidney disease related to the abnormal immunoglob vent progressive and irreversible kidney injury. ulin. If other, more likely causes of kidney injury are excluded 14

Multiple Myeloma and Related Disorders TABLE 9. Mayo Clinic Model of Risk of MGUS Progression to a Clinically Symptomatic Plasma Cell Dyscrasia Diagnosis Risk Factors Progression Non-light- M protein >1 .5 g/dl At 20 years: chain MGUS (lsG,lgA,lsM) Non-lgG M protein 3 RFs: 58% (high risk) Abnormal serum FLC ratio 2 RFs: 37% (high- intermediate risk) 1 RF:21"/o (intermed iate-low risk) 0 RFs: 5% (low risk) Smoldering M protein >3 g/dl At 5 years: myeloma Bone marrow 3 RFs: 76% plasma cells >1 0% 2 RFs: 51% Serum FLC ratio 1 RF:25/" <0.125 or>B mg/dL FLC = free light chain; MGUS = monoclonal gammopathy of undetermined significance; RF = risk factor. Data adapted from Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain rat o is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;1 06:8 1 2 17 .lPMlD: 1 58552741 doi: 1 0.1 1 B2,zblood-2005 03 1 038; and Dispenzieri A, Kyle RA, Katzmann JA, et al. lmmunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2008;11 1:785-9. IPMID: 17942755] doi:10.1 182lblood-2007,08 108357

Data adapted from Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain rat o is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;1 06:8 1 2 17 .lPMlD: 1 58552741 doi: 1 0.1 1 B2,zblood-2005 03 1 038; and Dispenzieri A, Kyle RA, Katzmann JA, et al. lmmunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2008;11 1:785-9. IPMID: 17942755] doi:10.1 182lblood-2007,08 108357 Multiple Myeloma MM is a clonal plasma cell neoplasm. MM can manifest as smoldering (asymptomatic) disease with risk of progression or symptomatic disease, which requires immediate treatment to prevent complications. Smoldering MM has a higher clonal plasma cell burden than MGUS and a higher risk of transfor- t I G U R E 7. Lytic bone lesions in a patient with multiple myeloma.The arrow mation to MM requiring therapy. denotes an oblique pathologic fracture through a mid-humerus lytic lesion.0ther lytic lesions can be seen both proximal and distal to the fracture. Clinical Manifestations and Findings MM requiring therapy manif'ests with classic symptoms such leads to hypercalcemia. Kidney dyslunction is seen in a signifi- as hypercalcemia, kidney disease, anemia, and bone disease cant proportion of patients. The two main causes of kidney (see CRAB and SLIM criteria in Table B). Other possible symp disease are elevated FLCs causing cast nephropathy and hyper toms include fatigue, weight loss, neuropathy, and those aris calcemia. Cast nephropathy, commonly termed mAeloma ing from extramedullary plasmacytoma. kidney, is caused by deposition of FLCs in the distal tubules, Normocytic anemia is a common finding in MM requiring leading to tubulointerstitial damage. Even with a normal base therapy. Anemia is caused by bone marrow plasma cell infil Iine creatinine level, underlying cast nephropathy makes these tration and kidney disease. The peripheral blood smear may patients especially vulnerable to additional kidney injury show rouleaux formation. Patients can also be immunosup through dehydration, NSAID use, or exposure to radioiodine pressed from leukopenia, impaired lymphocyte function, and contrast. Other causes of kidney dysfunction in patients with hypogammaglobulinemia (despite increased total immuno MM include immunoglobulin light-chain amyloidosis, cryo globulin, normal immunoglobulins are reduced). Patients are globulinemic glomerulonephritis, and proximal tubulopathy. at increased risk ofrespiratory infections, and chemotherapy for MM can further increase this risk. Diagnosis and Prognosis Bone pain is a common symptom of MM. Osteoclast Diagnostic criteria for MM are listed in Table B. Evaluating activation and osteoblast inactivation occur, leading to devel patients with suspected MM includes identifying the M pro- opment of lytic lesions (Figure 7) and vertebral body com- tein, assessing for symptoms of MM, and determining whether pression fracture. Patients with MM are prone to developing the symptoms are attributable to MM. Identification and pathologic fractures with minimal or no trauma. The quantiflcation of the M protein are accomplished with SPEP, increased bone resorption (together with kidney dysfunction) UPEB and serum FLC testing (see Evaluation for Monoclonal

Multiple Myeloma MM is a clonal plasma cell neoplasm. MM can manifest as smoldering (asymptomatic) disease with risk of progression or symptomatic disease, which requires immediate treatment to prevent complications. Smoldering MM has a higher clonal plasma cell burden than MGUS and a higher risk of transfor- t I G U R E 7. Lytic bone lesions in a patient with multiple myeloma.The arrow mation to MM requiring therapy. denotes an oblique pathologic fracture through a mid-humerus lytic lesion.0ther lytic lesions can be seen both proximal and distal to the fracture. Clinical Manifestations and Findings MM requiring therapy manif'ests with classic symptoms such leads to hypercalcemia. Kidney dyslunction is seen in a signifi- as hypercalcemia, kidney disease, anemia, and bone disease cant proportion of patients. The two main causes of kidney (see CRAB and SLIM criteria in Table B). Other possible symp disease are elevated FLCs causing cast nephropathy and hyper toms include fatigue, weight loss, neuropathy, and those aris calcemia. Cast nephropathy, commonly termed mAeloma ing from extramedullary plasmacytoma. kidney, is caused by deposition of FLCs in the distal tubules, Normocytic anemia is a common finding in MM requiring leading to tubulointerstitial damage. Even with a normal base therapy. Anemia is caused by bone marrow plasma cell infil Iine creatinine level, underlying cast nephropathy makes these tration and kidney disease. The peripheral blood smear may patients especially vulnerable to additional kidney injury show rouleaux formation. Patients can also be immunosup through dehydration, NSAID use, or exposure to radioiodine pressed from leukopenia, impaired lymphocyte function, and contrast. Other causes of kidney dysfunction in patients with hypogammaglobulinemia (despite increased total immuno MM include immunoglobulin light-chain amyloidosis, cryo globulin, normal immunoglobulins are reduced). Patients are globulinemic glomerulonephritis, and proximal tubulopathy. at increased risk ofrespiratory infections, and chemotherapy for MM can further increase this risk. Diagnosis and Prognosis Bone pain is a common symptom of MM. Osteoclast Diagnostic criteria for MM are listed in Table B. Evaluating activation and osteoblast inactivation occur, leading to devel patients with suspected MM includes identifying the M pro- opment of lytic lesions (Figure 7) and vertebral body com- tein, assessing for symptoms of MM, and determining whether pression fracture. Patients with MM are prone to developing the symptoms are attributable to MM. Identification and pathologic fractures with minimal or no trauma. The quantiflcation of the M protein are accomplished with SPEP, increased bone resorption (together with kidney dysfunction) UPEB and serum FLC testing (see Evaluation for Monoclonal 15

Multiple Myeloma and Related Disorders Gammopathies previously). Bone marrow biopsy is per this setting, including proteasome inhibitors (carfilzomib formed to evaluate the plasma cell burden and to determine and ixazomib). immunomodulatory drugs (pomalidomide cytogenetics for risk stratification. All patients are evaluated and. if not previously used, lenalidomide), histone deacetyl- for laboratory f'eatures of MM with complete blood count, ase inhibitors (panobinostat), alkylating agents (bendamus serum creatinine and calcium levels, and imaging studies. tine). and monoclonal antibodies (daratumumab, isatuximab, Whole-body, low dose CT (preferred) or PET-CT is recom- and elotuzumab). These agents are effective, and studies mended to detect lytic bone lesions in PCDs. If these modali continue to evaluate the best combinations and sequencing. ties are negative, a whole body MRI is recommended. Agents used to treat MM have unique adverse effects. MM Symptoms of organ dysfunction should not necessarily be increases the risk ol venous thromboembolism. and lenalido- attributed to the underlying PCD. Kidney biopsy is performed mide further increases this risk. Patients should receive Iow to document myeloma kidney when it is clinically difficult to dose aspirin il they do not have additional risk factors; patients differentiate kidney injury from another diagnosis, such as with additional risk tactors may require thromboprophylaxis. diabetic nephropathy. Evaluation for alternative causes of Bortezomib and thalidomide cause peripheral neuropathy. Many hypercalcemia and anemia should be completed, especially medications (proteasome inhibitors, daratumumab, isatuximab, when the patient has low-risk disease. and elotuzumab) are associated with a high risk of herpes zoster Smoldering MM has a risk of conversion to MM requiring reactivation, and prophylaxis with acyclovir is recommended. therapy of about 10'/, per year for the first 5 years. The risk of Pain is a prominent symptom in patients with MM requir progression decreases after the first 5 years. This risk is not uni ing therapy, and opioid treatment may be needed; NSAIDs can form; risk factors for progression include a high M protein level, worsen kidney clisease in these patients. Surgical stabilization a large burden of clonal plasma cells, and an abnormal serum of impending fiacture is undertaken to prevent morbidity. FLC ratio (see Table 9). Patients with MM who are at imminent Bisphosphonates (zoledronic acid and pamidronate) are used risk of progression in the next 2 years include those with 60% or to prevent skeletal events. Zoledronic acid has also been shown more plasma cells in the bone marrow more than one focal to improve survival in patients with MM requiring therapy. bone lesion on MRI, or a serum FLC ratio of 0.01 or less or 100 Patients taking bisphosphonates should be ciosely monitored or greater. These patients generally require prompt treatment. for kidney injury and osteonecrosis of the jaw. Patients should MM is staged based on the serum pr-microglobulin and notiff their dentist that they are receiving bisphosphonates and albumin. However, bone marrow cltogenetics more accurately have dental work done befbre treatment initiation, if possible. predict patient prognosis and guide better treatment decisions. Nephrotoxic agents and contrast studies should be used judiciously in patients with MM and a risk of worsening Treatment kidney disease. Hypercalcemia is treated with hydration and Patients with smoldering MM are usually monitored for pro bisphosphonates. Annual influenza vaccination (inactivated) gression to MM requiring therapy every 3 to 6 months. Studies should be administered to allpatients with MM. Because of the have shown improved survival with early treatment of high immunocompromised state ot' MM, pneumococcal vaccina risk smoldering MM, including in those at imminent risk of tion with the 13 valent pneumococcal conjugate vaccine and progression as defined previously. However, defining additional 23 valent pneumococcal polysaccharide vaccine should be categories of patients at high risk is somewhat controversial, administered in accordance with Advisory Committee on and it is not routine practice to treat them. Bisphosphonates do Immunization Practices guidelines (see MKSAP 19 General not decrease the risk of progression to MM. Internal Medicine 2). Select patients with recurrent infections 'l'reatment of MM requiring therapy has been revolution- and hypogammaglobulinemia benefit from intravenous ized over the last f'ew years with the advent of new treatment immune globulin inlusions. options. which have signiticantly improved survival (averaging XEY POIl{IS almost 10 years fiom diagnosis). Patients should initially be evaluated for autologous hematopoietic stem cell transplanta . Hypercalcemia, kidney disease, anemia, and bone disease tion (HSCT) eligibility. Autologous HSCT with high-dose mel- are classic symptoms of multiple myeloma requiring phalan is not curative but does improve progression free and therapy, which is defined by the presence of an M protein overall sunu'ival. Patients eligible for transplant typically and 10'1, or more clonal plasma or lymphoid cells in the undergo induction therapy with multiagent chemotherapy bone marrow. followed by autologous HSCT and maintenance therapy. . Smoldering multiple myeloma is defined by monoclonal Induction chemotherapy involves various combinations of immunoglobulin levels and the percentage of plasma cells immunomodulatory drugs (lenalidomide). proteasome inhib exceeding limits for monoclonal gammopathy of undeter itors (bortezomib), glucocorticoids (dexamethasone). alkylat- mined significance in patients with no disease-specific ing agents (melphalan or cyclophosphamide), and monoclonal symptoms; most of these patients do not require imme- antibodies (daratumumab). diate chemotherapy but should be closely monitored for Treatment is not curative, so all patients eventually disease progression. relapse or have refractory disease. Several drugs are used in Gontinued)

Gammopathies previously). Bone marrow biopsy is per this setting, including proteasome inhibitors (carfilzomib formed to evaluate the plasma cell burden and to determine and ixazomib). immunomodulatory drugs (pomalidomide cytogenetics for risk stratification. All patients are evaluated and. if not previously used, lenalidomide), histone deacetyl- for laboratory f'eatures of MM with complete blood count, ase inhibitors (panobinostat), alkylating agents (bendamus serum creatinine and calcium levels, and imaging studies. tine). and monoclonal antibodies (daratumumab, isatuximab, Whole-body, low dose CT (preferred) or PET-CT is recom- and elotuzumab). These agents are effective, and studies mended to detect lytic bone lesions in PCDs. If these modali continue to evaluate the best combinations and sequencing. ties are negative, a whole body MRI is recommended. Agents used to treat MM have unique adverse effects. MM Symptoms of organ dysfunction should not necessarily be increases the risk ol venous thromboembolism. and lenalido- attributed to the underlying PCD. Kidney biopsy is performed mide further increases this risk. Patients should receive Iow to document myeloma kidney when it is clinically difficult to dose aspirin il they do not have additional risk factors; patients differentiate kidney injury from another diagnosis, such as with additional risk tactors may require thromboprophylaxis. diabetic nephropathy. Evaluation for alternative causes of Bortezomib and thalidomide cause peripheral neuropathy. Many hypercalcemia and anemia should be completed, especially medications (proteasome inhibitors, daratumumab, isatuximab, when the patient has low-risk disease. and elotuzumab) are associated with a high risk of herpes zoster Smoldering MM has a risk of conversion to MM requiring reactivation, and prophylaxis with acyclovir is recommended. therapy of about 10'/, per year for the first 5 years. The risk of Pain is a prominent symptom in patients with MM requir progression decreases after the first 5 years. This risk is not uni ing therapy, and opioid treatment may be needed; NSAIDs can form; risk factors for progression include a high M protein level, worsen kidney clisease in these patients. Surgical stabilization a large burden of clonal plasma cells, and an abnormal serum of impending fiacture is undertaken to prevent morbidity. FLC ratio (see Table 9). Patients with MM who are at imminent Bisphosphonates (zoledronic acid and pamidronate) are used risk of progression in the next 2 years include those with 60% or to prevent skeletal events. Zoledronic acid has also been shown more plasma cells in the bone marrow more than one focal to improve survival in patients with MM requiring therapy. bone lesion on MRI, or a serum FLC ratio of 0.01 or less or 100 Patients taking bisphosphonates should be ciosely monitored or greater. These patients generally require prompt treatment. for kidney injury and osteonecrosis of the jaw. Patients should MM is staged based on the serum pr-microglobulin and notiff their dentist that they are receiving bisphosphonates and albumin. However, bone marrow cltogenetics more accurately have dental work done befbre treatment initiation, if possible. predict patient prognosis and guide better treatment decisions. Nephrotoxic agents and contrast studies should be used judiciously in patients with MM and a risk of worsening Treatment kidney disease. Hypercalcemia is treated with hydration and Patients with smoldering MM are usually monitored for pro bisphosphonates. Annual influenza vaccination (inactivated) gression to MM requiring therapy every 3 to 6 months. Studies should be administered to allpatients with MM. Because of the have shown improved survival with early treatment of high immunocompromised state ot' MM, pneumococcal vaccina risk smoldering MM, including in those at imminent risk of tion with the 13 valent pneumococcal conjugate vaccine and progression as defined previously. However, defining additional 23 valent pneumococcal polysaccharide vaccine should be categories of patients at high risk is somewhat controversial, administered in accordance with Advisory Committee on and it is not routine practice to treat them. Bisphosphonates do Immunization Practices guidelines (see MKSAP 19 General not decrease the risk of progression to MM. Internal Medicine 2). Select patients with recurrent infections 'l'reatment of MM requiring therapy has been revolution- and hypogammaglobulinemia benefit from intravenous ized over the last f'ew years with the advent of new treatment immune globulin inlusions. options. which have signiticantly improved survival (averaging XEY POIl{IS almost 10 years fiom diagnosis). Patients should initially be evaluated for autologous hematopoietic stem cell transplanta . Hypercalcemia, kidney disease, anemia, and bone disease tion (HSCT) eligibility. Autologous HSCT with high-dose mel- are classic symptoms of multiple myeloma requiring phalan is not curative but does improve progression free and therapy, which is defined by the presence of an M protein overall sunu'ival. Patients eligible for transplant typically and 10'1, or more clonal plasma or lymphoid cells in the undergo induction therapy with multiagent chemotherapy bone marrow. followed by autologous HSCT and maintenance therapy. . Smoldering multiple myeloma is defined by monoclonal Induction chemotherapy involves various combinations of immunoglobulin levels and the percentage of plasma cells immunomodulatory drugs (lenalidomide). proteasome inhib exceeding limits for monoclonal gammopathy of undeter itors (bortezomib), glucocorticoids (dexamethasone). alkylat- mined significance in patients with no disease-specific ing agents (melphalan or cyclophosphamide), and monoclonal symptoms; most of these patients do not require imme- antibodies (daratumumab). diate chemotherapy but should be closely monitored for Treatment is not curative, so all patients eventually disease progression. relapse or have refractory disease. Several drugs are used in Gontinued) 16

Multiple Myeloma and Related Disorders l,qIL[ ! *. TheAmyloidoses TyPe Disease Association Amyloid Protein AL amyloidosis Plasma cell dyscrasias (MGUS, multiple myeloma), Monoclonal free lr or r light chains Waldenstrom macroglobulinemia (rare) Hereditary amyloidosis lnherited Mutated TTR, fibrinogen o chain" AA amyloidosis Rheumatoid a.thritis, inflammatory bowel disease, familial Serum amyloid A protein Mediterranean fever, chronic in{ection Age-related (senile) amyloidosis Age Wild-type TTR Dialysis-related amyloidosis Dialysis for any reason p2-microglobulin AA = amyloid A (secondary) amyloidosis; AL = immunoglobulin light-chain amyloidosis; MGUS = monoclonal gammopathy of undetermined significance; TTR = transthyretin. "Not an all inclusive list.

l,qIL[ ! *. TheAmyloidoses TyPe Disease Association Amyloid Protein AL amyloidosis Plasma cell dyscrasias (MGUS, multiple myeloma), Monoclonal free lr or r light chains Waldenstrom macroglobulinemia (rare) Hereditary amyloidosis lnherited Mutated TTR, fibrinogen o chain" AA amyloidosis Rheumatoid a.thritis, inflammatory bowel disease, familial Serum amyloid A protein Mediterranean fever, chronic in{ection Age-related (senile) amyloidosis Age Wild-type TTR Dialysis-related amyloidosis Dialysis for any reason p2-microglobulin AA = amyloid A (secondary) amyloidosis; AL = immunoglobulin light-chain amyloidosis; MGUS = monoclonal gammopathy of undetermined significance; TTR = transthyretin. "Not an all inclusive list. lmmunoglobulin Light-Chain . Bisphosphonates should be routinely prescribed in Amyloidosis patients with myeloma requiring therapy because they Amyloidosis refers to a varied group of disorders associated prevent skeletal events and improve survival. with extracellular deposition of low-molecular-weight pro- . Patients with multiple myeloma eligible for transplant teins in a p-pleated sheet configuration. These are usually typically receive induction therapy with multiagent abnormal proteins that circulate in the blood and deposit in chemotherapy followed by autologous hematopoietic various organs. Various proteins have been implicated in amy- stem cell transplantation and maintenance therapy. loidosis (Table 1O). All amyloid deposits have a characteristic apple-green birefringence under polarized light microscopy of the tissue with Congo red staining. Light chain (AL) amyloidosis is the most common type. It is a clonal PCD characterized by production of amyloido- genic 1" or r FLCs. These light chains can deposit in the kid ney, heart, skin, liver, and other organs. Skin manifestations are present in 30%, to 40% ofpatients and include a general ized waxy appearance, easy bruising with minor pressure (pinch purpura), violaceous discoloration around the eyes ("raccoon eyes"), yellow waxy papules and plaques especially in a periorbital location (Figure 8), dystrophic nails, and macroglossia (Figure 9). Diagnosis requires biopsy of the

lmmunoglobulin Light-Chain . Bisphosphonates should be routinely prescribed in Amyloidosis patients with myeloma requiring therapy because they Amyloidosis refers to a varied group of disorders associated prevent skeletal events and improve survival. with extracellular deposition of low-molecular-weight pro- . Patients with multiple myeloma eligible for transplant teins in a p-pleated sheet configuration. These are usually typically receive induction therapy with multiagent abnormal proteins that circulate in the blood and deposit in chemotherapy followed by autologous hematopoietic various organs. Various proteins have been implicated in amy- stem cell transplantation and maintenance therapy. loidosis (Table 1O). All amyloid deposits have a characteristic apple-green birefringence under polarized light microscopy of the tissue with Congo red staining. Light chain (AL) amyloidosis is the most common type. It is a clonal PCD characterized by production of amyloido- genic 1" or r FLCs. These light chains can deposit in the kid ney, heart, skin, liver, and other organs. Skin manifestations are present in 30%, to 40% ofpatients and include a general ized waxy appearance, easy bruising with minor pressure (pinch purpura), violaceous discoloration around the eyes ("raccoon eyes"), yellow waxy papules and plaques especially in a periorbital location (Figure 8), dystrophic nails, and macroglossia (Figure 9). Diagnosis requires biopsy of the FIGURE 9. Macroglossiaisahallmarkfeatureoflight-chainamyloidosis.Heavy F I G U RE 8. A SO-year-old man with promi nent periorbital pur pura (black a nowsl infiltration of amyloid restricts longue mobility.The tongue cannot be extended, and yellow waxy papules and plaques. Abnormal coagulation and/or vessel fragility and obstruction of the pharynx causes problems with deglutition and breathing. leads to characteristic pinch purpura (white anow). Note the indentations from teeth pressing on the enlarged tongu e (arrow).

FIGURE 9. Macroglossiaisahallmarkfeatureoflight-chainamyloidosis.Heavy F I G U RE 8. A SO-year-old man with promi nent periorbital pur pura (black a nowsl infiltration of amyloid restricts longue mobility.The tongue cannot be extended, and yellow waxy papules and plaques. Abnormal coagulation and/or vessel fragility and obstruction of the pharynx causes problems with deglutition and breathing. leads to characteristic pinch purpura (white anow). Note the indentations from teeth pressing on the enlarged tongu e (arrow). 17

Multiple Myeloma and Related Disorders affected tissue showing characteristic pathological findings. performance status (independence completing activities of Abdominal fat pad or bone marrow biopsy may be preferred daily living) and the extent of organ involvement. Age is a initially to avoid invasive biopsy. After amyloid in the tissue is less important factor, and some centers perform transplan- confirmed, immunohistochemical staining can determine tation in patients up to age B0 years. Patients with advanced the light chain composition of the amyloid deposit or iden cardiac disease, stage 4 chronic kidney disease, or large tify alternative components, such as transthyretin or amyloid pleural effusions are generally not eligible for transplanta A protein. Patients with AL amyloidosis should undergo tion. Autologous HSCT has been shorvn to improve organ analysis for clonal PCDs with SPEP and UPEP. serum and function and survival. Patients ineligible for transplant urine immunofixation, serum FLC testing, bone marrow should receive treatment with agents used for myeloma biopsy, and imaging. therapy. Supportive care to treat symptoms (such as diuretics All patients are evaluated for extent of organ involve- for edema) is necessary. ment. Cardiac involvement is common with AL amyloidosis, The second most common type of amyloidosis is trans and evaluation typically includes echocardiography, electro- thyretin amyloid (wild type or variant transthyretin, see cardiography, B-type natriuretic peptide, and serum troponin Table 10), which deposits in the myocardium. It is estimated T. Cardiac MRI is more sensitive than echocardiography and that wild-type transthyretin amyloidosis (previously senile has a distinctive pattern. Kidney involvement usually mani systemic amyloidosis) may account for 10'/, of patients fests as nephrotic range proteinuria;24 hour urine protein who have heart failure with preserved ejection fraction. quantitation or a urine protein creatinine ratio assists diag Tafamidis is an oral agent shown to reduce mortality and nosis. Systemic amyloidosis with cutaneous involvement and improve quality of life in patients with transthyretin amy cutaneous amyloidosis are characterized by extracellular loid cardiomyopathy. deposition of altered amyloid protein in the skin, but the lat- rtY P0rilTs ter has a better prognosis, and patients may not require immediate therapy. Table 11 lists other potentially involved . Diagnosis of immunoglobulin light-chain amyloidosis organs and their clinical features. requires biopsy ofthe affected tissue showing character- Prognosis depends on the presence and extent ofcardiac istic pathological findings of apple-green birefringence involvement; survival ranges from almost B years to only under polarized Iight microscopy of the tissue with Congo red staining; immunohistochemical staining then 6 months. Treatment starts with evaluating the patient for autolo- determines the light-chain nature of the amyloid. (Continued) gous HSCT. Eligibility for transplantation is based on

affected tissue showing characteristic pathological findings. performance status (independence completing activities of Abdominal fat pad or bone marrow biopsy may be preferred daily living) and the extent of organ involvement. Age is a initially to avoid invasive biopsy. After amyloid in the tissue is less important factor, and some centers perform transplan- confirmed, immunohistochemical staining can determine tation in patients up to age B0 years. Patients with advanced the light chain composition of the amyloid deposit or iden cardiac disease, stage 4 chronic kidney disease, or large tify alternative components, such as transthyretin or amyloid pleural effusions are generally not eligible for transplanta A protein. Patients with AL amyloidosis should undergo tion. Autologous HSCT has been shorvn to improve organ analysis for clonal PCDs with SPEP and UPEP. serum and function and survival. Patients ineligible for transplant urine immunofixation, serum FLC testing, bone marrow should receive treatment with agents used for myeloma biopsy, and imaging. therapy. Supportive care to treat symptoms (such as diuretics All patients are evaluated for extent of organ involve- for edema) is necessary. ment. Cardiac involvement is common with AL amyloidosis, The second most common type of amyloidosis is trans and evaluation typically includes echocardiography, electro- thyretin amyloid (wild type or variant transthyretin, see cardiography, B-type natriuretic peptide, and serum troponin Table 10), which deposits in the myocardium. It is estimated T. Cardiac MRI is more sensitive than echocardiography and that wild-type transthyretin amyloidosis (previously senile has a distinctive pattern. Kidney involvement usually mani systemic amyloidosis) may account for 10'/, of patients fests as nephrotic range proteinuria;24 hour urine protein who have heart failure with preserved ejection fraction. quantitation or a urine protein creatinine ratio assists diag Tafamidis is an oral agent shown to reduce mortality and nosis. Systemic amyloidosis with cutaneous involvement and improve quality of life in patients with transthyretin amy cutaneous amyloidosis are characterized by extracellular loid cardiomyopathy. deposition of altered amyloid protein in the skin, but the lat- rtY P0rilTs ter has a better prognosis, and patients may not require immediate therapy. Table 11 lists other potentially involved . Diagnosis of immunoglobulin light-chain amyloidosis organs and their clinical features. requires biopsy ofthe affected tissue showing character- Prognosis depends on the presence and extent ofcardiac istic pathological findings of apple-green birefringence involvement; survival ranges from almost B years to only under polarized Iight microscopy of the tissue with Congo red staining; immunohistochemical staining then 6 months. Treatment starts with evaluating the patient for autolo- determines the light-chain nature of the amyloid. (Continued) gous HSCT. Eligibility for transplantation is based on TAELE 1 1. Clinical Manifestations of ALAmyloidosis by Organ System OrganSystem ClinicalManifestations Findings Kidney Anasarca, lower extremity edema, foamy urine Nephrotic range proteinuria with bland urine sediment, hypoalbuminemia, elevated serum creatinine, nephromegaly on kidney ultrasonography Gastrointestina I Gastrointestinal bleeding, dysphagia, early satiety, Anemia, iron deficiency, submucosal hematomas on abdominal distention, steatorrhea endoscopy, hypoalbuminemia, delayed gastric emptying, intestinal pseudo-obstruction, malabsorption, small intestinal bacterial overgrowth Liver Weight loss, abdominal pain, features of chronic Cholestatic liver test abnormalities, hepatosplenomegaly, liver disease and portal hypertension evidence of portal hypertension i Neurologic Distal numbness, paresthesias, neuropathic pain, Dista I sensorimotor polyneu ropathy on electromyogra phy/ weakness, autonom ic nerve dysfunction nerve conduction studies, autonomic neuropathy Card ac Chest pain, symptoms from chronic heart failure or Echocardiographic changes (ventricular hypertrophy with arrhythmia granular appearance, restrictive cardiomyopathy with HFpEF more common than HFrEF), electrocardiographic changes (low voltages, pseudoinfarct pattern, conduction system changes, arrhythmias), abnormal cardiac MRI (late gadolinium enhancement) Coag u lation Bleeding diathesis, periorbital purpura, pinch Factor X deficiency with prolonged PT and aPTT, purpura (see Figure B) prolonged PTand aPTTfrom advanced liver impairment, blood vessel fragility from vascular amyloid deposition Musculoskeletal Macroglossia (see Figure 9), muscle lmpaired median nerve conduction across the carpal pseudohyper.trophy, symmetric arthropathy, tunnel, joint space widening on plain radiographs, submandibular gland enlargement, carpal tunnel periarticular soft tissue and muscle infiltration on MRI syndrome

TAELE 1 1. Clinical Manifestations of ALAmyloidosis by Organ System OrganSystem ClinicalManifestations Findings Kidney Anasarca, lower extremity edema, foamy urine Nephrotic range proteinuria with bland urine sediment, hypoalbuminemia, elevated serum creatinine, nephromegaly on kidney ultrasonography Gastrointestina I Gastrointestinal bleeding, dysphagia, early satiety, Anemia, iron deficiency, submucosal hematomas on abdominal distention, steatorrhea endoscopy, hypoalbuminemia, delayed gastric emptying, intestinal pseudo-obstruction, malabsorption, small intestinal bacterial overgrowth Liver Weight loss, abdominal pain, features of chronic Cholestatic liver test abnormalities, hepatosplenomegaly, liver disease and portal hypertension evidence of portal hypertension i Neurologic Distal numbness, paresthesias, neuropathic pain, Dista I sensorimotor polyneu ropathy on electromyogra phy/ weakness, autonom ic nerve dysfunction nerve conduction studies, autonomic neuropathy Card ac Chest pain, symptoms from chronic heart failure or Echocardiographic changes (ventricular hypertrophy with arrhythmia granular appearance, restrictive cardiomyopathy with HFpEF more common than HFrEF), electrocardiographic changes (low voltages, pseudoinfarct pattern, conduction system changes, arrhythmias), abnormal cardiac MRI (late gadolinium enhancement) Coag u lation Bleeding diathesis, periorbital purpura, pinch Factor X deficiency with prolonged PT and aPTT, purpura (see Figure B) prolonged PTand aPTTfrom advanced liver impairment, blood vessel fragility from vascular amyloid deposition Musculoskeletal Macroglossia (see Figure 9), muscle lmpaired median nerve conduction across the carpal pseudohyper.trophy, symmetric arthropathy, tunnel, joint space widening on plain radiographs, submandibular gland enlargement, carpal tunnel periarticular soft tissue and muscle infiltration on MRI syndrome 18

Erythrocyte Disorders l(EV POI t{TS kontinaed} antibodies against eq,{hroc},te antigens that agglutinate erythro . Patients with immunoglobulin light-chain amyloidosis cltes in blood at temperatures less than 37 'C (98.6 'F) and can sometimes cause cold agglutinin autoimmune hemolytic who are ineligible for autologous hematopoietic stem anemia. cell transplantation should receive treatment with agents Cryoglobulinemia is classified as type I, II, or III based on used in multiple myeloma. the composition of the cryoglobulin. Type I involves a mono clonal immunoglobulin, usually IgM, and is associated with PCDs. Types II and lll are called mixed cryoglobulinemias; Waldenstrtim Macrog lobulinemia they are composed of a mixture of polyclonal lgG and mono Waldenstrom macroglobulinemia (WM) is an indolent B cell clonal or polyclonal IgM. Mixed cryoglobulinemias are usually lymphoma with clonal tymphoplasmacytic cells in the bone seen in association with infections such as hepatitis C, with marrow or lymph nodes that secrete clonal IgM into the blood. connective tissue disorders, and rarely with lymphoprolif'era WM is differentiated from MGUS by the presence of more than tive disorders. 107, clonal Iymphopiasmacytic cells in the bone marrow Type I is usually asymptomatic but can rarely cause greater than 3 g/dl of M protein, symptoms from the disease, symptoms of hyperviscosity and thrombosis. Patients can or a combination of the three. As in MM, patients with smold present with digital cyanosis, ulcers, Raynaud phenomenon, 'r ering, asymptomatic WM can be observed without therapy. or gangrene. Patients with neurologic symptoms from hyper l. Patients can present with classic "B symptoms" of drench viscosity undergo emergent plasmapheresis, along with treat ing night sweats, fever, and weight loss and may have anemia ment of the underlying plasma cell dyscrasia to prevent and fatigue. Tissue infiltration leads to hepatosplenomegaly, cryoglobulin production. Vasculitic symptoms, such as palpa lymphadenopathy, gastrointestinal dysfunction, and kidney ble purpura, glomerulonephritis, and neuropathy, are less disease. Peripheral sensorimotor neuropathy is seen in 2O"/,, of common in patients with type I (see MKSAP 19 Rheumatologr patients and can be associated u'ith antimyelin associated for further information on mixed cryoglobulinemias). glycoprotein. Increased serum viscosity from the circulating IgM can lead to hyperviscosity syndrome, which can include t(EY POtl{Tt diverse central nervous system symptoms, including head . Type I cryoglobulinemia involves a monoclonal immu ache, altered mental status, change in vision and hearing, noglobulin (usually IgM), is associated with plasma cell nystagmus, and ataxia. Funduscopic evaluation may reveal dyscrasias, and patients are typically asymptomatic. dilated retinal veins. papilledema, and flame hemorrhages. . Tlpes II and III mixed cryoglobulinemias are composed of Mucosal bleeding is related to platelet dysfunction and dysfi a mixture of polyclonal IgG and monoclonal or polyclonal brinogenemia (prolonged thrombin time). IgM and are usually seen in association with hepatitis C, Symptomatic hyperviscosity requires emergent treatment connective tissue disorders, or lymphoproliferative with plasmapheresis to remove excess IgM. Therapy to disorders. decrease IgM production is instituted simultaneously in patients with hyperviscosity symptoms and should be initi ated in other patients with symptomatic WM. Rituximab in combination with chemotherapy such as cyclophosphamide and bortezomib, along with glucocorticoids, is commonly Erythrocyte Disorders used. Approach to Anemia XEY POITT Anemia is a pathologic state resulting in an insufficient num r Patients with Waldenstrom macroglobulinemia with ber of erythrocytes to deliver oxygen to organs and tissues. Anemia can arise from blood loss, erythrocyte underproduc- hyperviscosity syndrome, characterized by altered men- tion, erythrocyte destruction (hemolysis), or a combination of tal status and diverse central nervous system symptoms, these factors. Patients with anemia may be entirely asympto dilated retinal veins on funduscopic examination, and matic or may experience symptoms of dyspnea, decreased mucosal bleeding from impaired platelet function and exercise tolerance, palpitations, lightheadedness, or fatigue. dysfibrinogenemia, require emergent plasmapheresis to Symptoms generally reflect the degree of anemia and how remove excess IgM. quickly anemia develops; they are also determined by end organ function and vascular disease. From a laboratory perspective, the automated complete Cryoglobulinemia blood count (CBC) identifies the severity of the anemia. The Cryoglobulinemia denotes the presence of clonal or polyclonal CBC includes the inter related erythrocyte count, hematocrit immunoglobulins that precipitate in the serum at temperatures (percentage of blood volume composed of erythrocytes), less than 37 'C (98.6 'F) and dissolve with rewarming. Cold and hemoglobin concentration and erythrocyte indices, such egglutinins, which are often confused with cryoglobulins, are as the mean corpuscular volume (MCV) and the red cell

. Patients with immunoglobulin light-chain amyloidosis cltes in blood at temperatures less than 37 'C (98.6 'F) and can sometimes cause cold agglutinin autoimmune hemolytic who are ineligible for autologous hematopoietic stem anemia. cell transplantation should receive treatment with agents Cryoglobulinemia is classified as type I, II, or III based on used in multiple myeloma. the composition of the cryoglobulin. Type I involves a mono clonal immunoglobulin, usually IgM, and is associated with PCDs. Types II and lll are called mixed cryoglobulinemias; Waldenstrtim Macrog lobulinemia they are composed of a mixture of polyclonal lgG and mono Waldenstrom macroglobulinemia (WM) is an indolent B cell clonal or polyclonal IgM. Mixed cryoglobulinemias are usually lymphoma with clonal tymphoplasmacytic cells in the bone seen in association with infections such as hepatitis C, with marrow or lymph nodes that secrete clonal IgM into the blood. connective tissue disorders, and rarely with lymphoprolif'era WM is differentiated from MGUS by the presence of more than tive disorders. 107, clonal Iymphopiasmacytic cells in the bone marrow Type I is usually asymptomatic but can rarely cause greater than 3 g/dl of M protein, symptoms from the disease, symptoms of hyperviscosity and thrombosis. Patients can or a combination of the three. As in MM, patients with smold present with digital cyanosis, ulcers, Raynaud phenomenon, 'r ering, asymptomatic WM can be observed without therapy. or gangrene. Patients with neurologic symptoms from hyper l. Patients can present with classic "B symptoms" of drench viscosity undergo emergent plasmapheresis, along with treat ing night sweats, fever, and weight loss and may have anemia ment of the underlying plasma cell dyscrasia to prevent and fatigue. Tissue infiltration leads to hepatosplenomegaly, cryoglobulin production. Vasculitic symptoms, such as palpa lymphadenopathy, gastrointestinal dysfunction, and kidney ble purpura, glomerulonephritis, and neuropathy, are less disease. Peripheral sensorimotor neuropathy is seen in 2O"/,, of common in patients with type I (see MKSAP 19 Rheumatologr patients and can be associated u'ith antimyelin associated for further information on mixed cryoglobulinemias). glycoprotein. Increased serum viscosity from the circulating IgM can lead to hyperviscosity syndrome, which can include t(EY POtl{Tt diverse central nervous system symptoms, including head . Type I cryoglobulinemia involves a monoclonal immu ache, altered mental status, change in vision and hearing, noglobulin (usually IgM), is associated with plasma cell nystagmus, and ataxia. Funduscopic evaluation may reveal dyscrasias, and patients are typically asymptomatic. dilated retinal veins. papilledema, and flame hemorrhages. . Tlpes II and III mixed cryoglobulinemias are composed of Mucosal bleeding is related to platelet dysfunction and dysfi a mixture of polyclonal IgG and monoclonal or polyclonal brinogenemia (prolonged thrombin time). IgM and are usually seen in association with hepatitis C, Symptomatic hyperviscosity requires emergent treatment connective tissue disorders, or lymphoproliferative with plasmapheresis to remove excess IgM. Therapy to disorders. decrease IgM production is instituted simultaneously in patients with hyperviscosity symptoms and should be initi ated in other patients with symptomatic WM. Rituximab in combination with chemotherapy such as cyclophosphamide and bortezomib, along with glucocorticoids, is commonly Erythrocyte Disorders used. Approach to Anemia XEY POITT Anemia is a pathologic state resulting in an insufficient num r Patients with Waldenstrom macroglobulinemia with ber of erythrocytes to deliver oxygen to organs and tissues. Anemia can arise from blood loss, erythrocyte underproduc- hyperviscosity syndrome, characterized by altered men- tion, erythrocyte destruction (hemolysis), or a combination of tal status and diverse central nervous system symptoms, these factors. Patients with anemia may be entirely asympto dilated retinal veins on funduscopic examination, and matic or may experience symptoms of dyspnea, decreased mucosal bleeding from impaired platelet function and exercise tolerance, palpitations, lightheadedness, or fatigue. dysfibrinogenemia, require emergent plasmapheresis to Symptoms generally reflect the degree of anemia and how remove excess IgM. quickly anemia develops; they are also determined by end organ function and vascular disease. From a laboratory perspective, the automated complete Cryoglobulinemia blood count (CBC) identifies the severity of the anemia. The Cryoglobulinemia denotes the presence of clonal or polyclonal CBC includes the inter related erythrocyte count, hematocrit immunoglobulins that precipitate in the serum at temperatures (percentage of blood volume composed of erythrocytes), less than 37 'C (98.6 'F) and dissolve with rewarming. Cold and hemoglobin concentration and erythrocyte indices, such egglutinins, which are often confused with cryoglobulins, are as the mean corpuscular volume (MCV) and the red cell 19