Chapter 106. Plasma Cell Disorders (Part 4)

Bone pain is the most common symptom in myeloma, affecting nearly 70% of patients. The pain usually involves the back and ribs, and unlike the pain of metastatic carcinoma, which often is worse at night, the pain of myeloma is precipitated by movement. Persistent localized pain in a patient with myeloma usually signifies a pathologic fracture. The bone lesions of myeloma are caused by the proliferation of tumor cells, activation of osteoclasts that destroy bone, and suppression of osteoblasts that form new bone. The osteoclasts respond to osteoclast activating factors (OAF) made by the myeloma cells [OAF activity can...
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Chapter 106. Plasma Cell Disorders (Part 4) Chapter 106. Plasma Cell Disorders (Part 4) Bone pain is the most common symptom in myeloma, affecting nearly 70%of patients. The pain usually involves the back and ribs, and unlike the pain ofmetastatic carcinoma, which often is worse at night, the pain of myeloma isprecipitated by movement. Persistent localized pain in a patient with myelomausually signifies a pathologic fracture. The bone lesions of myeloma are caused bythe proliferation of tumor cells, activation of osteoclasts that destroy bone, andsuppression of osteoblasts that form new bone. The osteoclasts respond toosteoclast activating factors (OAF) made by the myeloma cells [OAF activity canbe mediated by several cytokines, including IL-1, lymphotoxin, VEGF, receptoractivator of NF-κB (RANK) ligand, macrophage inhibitory factor (MIP)-1α, andtumor necrosis factor (TNF)]. However, production of these factors decreasesfollowing administration of glucocorticoids or interferon (IFN) α. The bonelesions are lytic in nature and are rarely associated with osteoblastic new boneformation. Therefore, radioisotopic bone scanning is less useful in diagnosis thanis plain radiography. The bony lysis results in substantial mobilization of calciumfrom bone, and serious acute and chronic complications of hypercalcemia maydominate the clinical picture (see below). Localized bone lesions may expand tothe point that mass lesions may be palpated, especially on the skull (Fig. 106-4),clavicles, and sternum, and the collapse of vertebrae may lead to spinal cordcompression. Figure 106-4 Bony lesions in multiple myeloma. The skull demonstrates the typicalpunched out lesions characteristic of multiple myeloma. The lesion represents apurely osteolytic lesion with little or no osteoblastic activity. (Courtesy of Dr.Geraldine Schechter; with permission.) The next most common clinical problem in patients with myeloma issusceptibility to bacterial infections. The most common infections are pneumoniasand pyelonephritis, and the most frequent pathogens are Streptococcuspneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs andEscherichia coli and other gram-negative organisms in the urinary tract. In ~25%of patients, recurrent infections are the presenting features, and >75% of patientswill have a serious infection at some time in their course. The susceptibility toinfection has several contributing causes. First, patients with myeloma havediffuse hypogammaglobulinemia if the M component is excluded. Thehypogammaglobulinemia is related to both decreased production and increaseddestruction of normal antibodies. Moreover, some patients generate a populationof circulating regulatory cells in response to their myeloma that can suppressnormal antibody synthesis. In the case of IgG myeloma, normal IgG antibodies arebroken down more rapidly than normal because the catabolic rate for IgGantibodies varies directly with the serum concentration. The large M componentresults in fractional catabolic rates of 8–16% instead of the normal 2%. Thesepatients have very poor antibody responses, especially to polysaccharide antigenssuch as those on bacterial cell walls. Most measures of T cell function in myelomaare normal, but a subset of CD4+ cells may be decreased. Granulocyte lysozymecontent is low, and granulocyte migration is not as rapid as normal in patients withmyeloma, probably the result of a tumor product. There are also a variety ofabnormalities in complement functions in myeloma patients. All these factorscontribute to the immune deficiency of these patients. Some commonly usedtherapeutic agents, e.g., dexamethasone, suppress immune responses and increasesusceptibility to infection. Renal failure occurs in nearly 25% of myeloma patients, and some renalpathology is noted in over half. Many factors contribute to this. Hypercalcemia isthe most common cause of renal failure. Glomerular deposits of amyloid,hyperuricemia, recurrent infections, frequent use of nonsteroidal anti-inflammatory agents for pain control, use of iodinated contrast dye for imaging,bisphosphonate use, and occasional infiltration of the kidney by myeloma cells allmay contribute to renal dysfunction. However, tubular damage associated with theexcretion of light chains is almost always present. Normally, light chains arefiltered, reabsorbed in the tubules, and catabolized. With the increase in theamount of light chains presented to the tubule, the tubular cells becomeoverloaded with these proteins, and tubular damage results either directly fromlight chain toxic effects or indirectly from the release of intracellular lysosomalenzymes. The earliest manifestation of this tubular damage is the adult F ...