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ESSENTIALS OF DIAGNOSIS

  • Bone pain, often in the spine, ribs, or proximal long bones.

  • Monoclonal immunoglobulin (ie, paraprotein) in the serum or urine.

  • Clonal plasma cells in the bone marrow or in a tissue biopsy, or both.

  • Organ damage due to plasma cells (eg, bones, kidneys, hypercalcemia, anemia) or other defined criteria.

GENERAL CONSIDERATIONS

Plasma cell myeloma (previously called multiple myeloma) is a malignancy of hematopoietic stem cells terminally differentiated as plasma cells characterized by infiltration of the bone marrow, bone destruction, and paraprotein formation. The diagnosis is established when monoclonal plasma cells (either kappa or lambda light chain restricted) in the bone marrow (any percentage) or as a tumor (plasmacytoma), or both, are associated with end-organ damage (such as bone disease [lytic lesions seen on bone radiographs, magnetic resonance imaging {MRI}, or PET/CT scan], anemia [hemoglobin less than 10 g/dL {100 g/L}], hypercalcemia [calcium greater than 11.5 mg/dL {2.9 mmol/L}], or kidney injury [creatinine greater than 2 mg/dL {176.8 mcmol/L}]) with or without paraprotein elaboration. Sixty percent or more clonal plasma cells in the bone marrow, or a serum free kappa to lambda ratio of greater than 100 or less than 0.01 (both criteria regardless of end-organ damage), are also diagnostic of plasma cell myeloma. Smoldering myeloma is defined as 10–59% clonal plasma cells in the bone marrow, a serum paraprotein level of 3 g/dL (30 g/L) or higher, or both, without plasma cell–related end-organ damage.

Malignant plasma cells can form tumors (plasmacytomas) that may cause spinal cord compression or other soft-tissue–related problems. Bone disease is common and due to excessive osteoclast activation mediated largely by the interaction of the receptor activator of NF-kappa-B (RANK) with its ligand (RANKL). In plasma cell myeloma, osteoprotegerin (a decoy receptor for RANKL) is underproduced, thus promoting the binding of RANK with RANKL with consequent excessive bone resorption. Other soluble factors contributing to osteoclast hyperactivation include interleukin-1, interleukin-6, tissue necrosis factor-alpha, macrophage inhibitor protein-1-alpha, and macrophage colony stimulating factor, all of which might prove eventual therapeutic targets.

The paraproteins (monoclonal immunoglobulins) secreted by the malignant plasma cells may cause problems in their own right. Very high paraprotein levels (either IgG or IgA) may cause hyperviscosity, although this is more common with the IgM paraprotein in Waldenström macroglobulinemia. The light chain component of the immunoglobulin, when produced in excess, often leads to kidney injury (frequently aggravated by hypercalcemia or hyperuricemia, or both). Light chain components may be deposited in tissues as amyloid, resulting in kidney failure with albuminuria and a vast array of systemic symptoms.

Myeloma patients are prone to recurrent infections for a number of reasons, including neutropenia, the underproduction of normal immunoglobulins and the immunosuppressive effects of chemotherapy. Myeloma patients are especially prone to infections with encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae.

CLINICAL FINDINGS

A. Symptoms and Signs

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