Chapter 106. Plasma Cell Disorders (Part 5) Anemia occurs in ~80% of myeloma patients. It is usually normocytic and normochromic and related both to the replacement of normal marrow by expanding tumor cells and to the inhibition of hematopoiesis by factors made by the tumor. In addition, mild hemolysis may contribute to the anemia. A larger than expected fraction of patients may have megaloblastic anemia due to either folate or vitamin B 12 deficiency. Granulocytopenia and thrombocytopenia are very rare. Clotting abnormalities may be seen due to the failure of antibody-coated platelets to function properly or to the interaction of the M component with clotting factors I, II, V, VII, or VIII. Deep venous thrombosis is also observed with use of thalidomide or lenalidomide in combination with dexamethasone. Raynaud's phenomenon and impaired circulation may result if the M component forms cryoglobulins, and hyperviscosity syndromes may develop depending on the physical properties of the M component (most common with IgM, IgG3, and IgA paraproteins). Hyperviscosity is defined on the basis of the relative viscosity of serum as compared with water. Normal relative serum viscosity is 1.8 (i.e., serum is normally almost twice as viscous as water). Symptoms of hyperviscosity occur at a level of 5–6, a level usually reached at paraprotein concentrations of ~40 g/L (4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA. Although neurologic symptoms occur in a minority of patients, they may have many causes. Hypercalcemia may produce lethargy, weakness, depression, and confusion. Hyperviscosity may lead to headache, fatigue, visual disturbances, and retinopathy. Bony damage and collapse may lead to cord compression, radicular pain, and loss of bowel and bladder control. Infiltration of peripheral nerves by amyloid can be a cause of carpal tunnel syndrome and other sensorimotor mono- and polyneuropathies. Sensory neuropathy is also a side effect of thalidomide and bortezomib therapy. Many of the clinical features of myeloma, e.g., cord compression, pathologic fractures, hyperviscosity, sepsis, and hypercalcemia, can present as medical emergencies. Despite the widespread distribution of plasma cells in the body, tumor expansion is dominantly within bone and bone marrow and, for reasons unknown, rarely causes enlargement of spleen, lymph nodes, or gut- associated lymphatic tissue. Diagnosis and Staging The classic triad of myeloma is marrow plasmacytosis (>10%), lytic bone lesions, and a serum and/or urine M component. Bone marrow plasma cells are CD138+ and monoclonal. The most important differential diagnosis in patients with myeloma involves their separation from individuals with monoclonal gammopathies of uncertain significance (MGUS). MGUS are vastly more common than myeloma, occurring in 1% of the population over age 50 and in up to 10% individuals over age 75. The diagnostic criteria for MGUS, smoldering myeloma, and myeloma are described in Table 106-2. When bone marrow cells are exposed to radioactive thymidine in order to quantitate dividing cells, patients with MGUS always have a labeling index < 1%; patients with myeloma always have a labeling index > 1%. With long-term follow-up, ~1% per year of patients with MGUS go on to develop myeloma. Non-IgG subtype, abnormal kappa/lambda free light chain ratio, and serum M protein > 15 g/L (1.5 g/dL) are associated with higher incidence of progression of MGUS to myeloma. Typically, patients with MGUS require no therapy. Their survival is ~2 years shorter than age-matched controls without MGUS. There are two important variants of myeloma, solitary bone plasmacytoma and extramedullary plasmacytoma. These lesions are associated with an M component in <30% of the cases, they may affect younger individuals, and both are associated with median survivals of ≥10 years. Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis. Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis. Both tumors are highly responsive to local radiation therapy. If an M component is present, it should disappear after treatment. Solitary bone plasmacytomas may recur in other bony sites or evolve into myeloma. Extramedullary plasmacytomas rarely recur or progress. Table 106- 2 Diagnostic Criteria for Multiple Myeloma, Myeloma Variants, and Monoclonal Gammopathy of Unknown Significance Monoclonal gammopathy of undetermined significance (MGUS) M protein in serum < 30 g/L Bone marrow clonal plasma cells < 10% No evidence of other B cell proliferative disorders No myeloma- related organ or tissue impairment (no end organ damage, including bone lesions) a Asymptomatic myeloma (smouldering myeloma) M protein in serum ≥30 g/L and/or Bone marrow clonal plasma cells ≥10% No myeloma- related organ or tissue impairment (no end organ damage, including bone lesions) a or symptoms Symptomatic multiple myeloma M protein in serum and/or urine Bone marrow (clonal) plasma cells b or plasmacytoma Myeloma- related organ or tissue impairment (end organ damage, including bone lesions) Nonsecretory myeloma No M protein in serum and/or urine with immunofixation Bone marrow clonal plasmacytosis ≥10% or plasmacytoma Myeloma- related organ or tissue impairment (end organ damage, including bone lesions) a Solitary plasmacytoma of bone No M protein in serum and/or urine c Single area of bone destruction due to clonal plasma cells Bone marrow not consistent with multiple myeloma Normal skeletal survey (and MRI of spine and pelvis if done) No related organ or tissue impairment (no end organ damage other than solitary bone lesion) a a Myeloma-related organ or tissue impairment (end organ damage) (ROTI ): Calcium levels increased: serum calcium > 0.25 mmol/L above the upper limit of normal or > 2.75 mmol/L; renal insufficiency: creatinine > 173 mmol/L; anemia: hemoglobin 2 g/dL below the lower limit of normal or hemoglobin < 10 g/dL; bone lesions: lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify); other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (>2 episodes in 12 months). b If flow cytometry is performed, most plasma cells (>90%) will show a "neoplastic" phenotype. c A small M component may sometimes be present. . Chapter 106. Plasma Cell Disorders (Part 5) Anemia occurs in ~80% of myeloma patients. It is usually normocytic and. significance (MGUS) M protein in serum < 30 g/L Bone marrow clonal plasma cells < 10% No evidence of other B cell proliferative disorders No myeloma- related organ or tissue impairment (no. myeloma, and myeloma are described in Table 106- 2. When bone marrow cells are exposed to radioactive thymidine in order to quantitate dividing cells, patients with MGUS always have a labeling