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Chapter 86 Plasma Cell Neoplasms 1391

TABLE Clinical Features of Multiple Myeloma Its occurrence is related to bone involvement as well as production
86.4 of various cytokines that lead to increased bone resorption and
calcium release. Hypercalcemia manifests as mental status changes,
Bone Destruction Marrow Infiltration lethargy, nausea and vomiting, and constipation. In extreme cases, a
Pain Anemia patient can also develop seizure activity. A normal serum calcium level
Fractures Bleeding tendency in the presence of high paraprotein and/or low albumen level may
Cord compression Reduced Globulins require calculation or measurement of ionized calcium levels to assess
Radicular pain Recurrent infections true and effective serum calcium levels. Hypercalcemia can also
Hypercalcemia Pneumonia induce renal failure caused by dehydration, and it is to be considered
Polyuria, polydipsia Cryoglobulins a hematologic emergency meriting prompt intervention.
Nausea, vomiting Raynaud’s phenomenon
Renal Failure Acrocyanosis
Nausea, vomiting Hyperviscosity Renal Failure
Malaise, weakness Shortness of breath
Amyloidosis Transient ischemic attacks Renal insufficiency is a frequent and serious complication of myeloma
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that has a multifactorial etiology. The most common and reversible
Peripheral neuropathy Deep vein thrombosis cause of renal failure is light chain tubular cast deposition and/or light
Dependent edema Retinal hemorrhage chain deposition disease (commonly associated with κ light chains).
Organomegaly Epistaxis Similarly, proteins can be deposited as amyloid, predominantly
involving λ light chains (specifically λ light chain subtype 6) with
development of kidney failure. Amyloidosis is quite often associated
the basis of routine blood work. The symptoms may also be related with nephrotic syndrome range proteinuria. The proteinuria observed
either to deposition of paraproteins in various organs as either light in patients with amyloid is more nonspecific, which differs from
chain or amyloid deposits or to cytokines such as IL-6 or VEGF conditions with light chain cast nephropathy with predominantly
produced by the myeloma cells and/or the BMSCs. Owing to excess of light chain excretion in the urine. Another common cause
improvement in routine blood work and availability of sensitive tests, is hypercalcemia leading to osmotic diuresis and prerenal dysfunction
the clinical presentation in myeloma has changed over the last 25 associated with volume depletion. Additional mechanisms of renal
years. Overall, patients are more frequently being diagnosed with failure in myeloma include renal calcium deposition with interstitial
asymptomatic disease rather than on the basis of presenting symp- nephritis, use of nonsteroidal antiinflammatory drugs for pain
toms. For example, patients present less often with bone pain, control, hyperuricemia, intravenous contrast dye use for imaging
pathologic fractures, renal failure, or hyperviscosity. Various clinical purposes, chemotherapy-induced nephrotoxicity, and use of bisphos-
features of myeloma are summarized in Table 86.4. phonates. The development of light chain deposition disease has been
reported to be associated with Tamm-Horsfall protein, which pro-
motes heterotypic aggregation of light chains with deposition in the
Bone Disease kidneys. Patients with renal failure are quite asymptomatic. However,
when symptoms are present, they are predominately malaise, weak-
Almost two-thirds of patients with MM present with bone pain ness, nausea, or vomiting.
as their main symptom. The mechanism of bone involvement is
multifactorial, including direct bone destruction by the unbalanced
hyperactivity of OCs and suppression of osteoblastic activity. This Anemia
is further accentuated by the cytokine milieu generated in the bone
marrow microenvironment by interaction between myeloma cells Anemia is another presenting symptom of myeloma and is symptom-
and BMSCs, which includes IL-6, IL-1β, TNF-α, and macrophage atically associated with fatigue and shortness of breath. The anemia
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inflammatory protein 1α. A member of the TNF family, receptor usually is normochromic and normocytic and has a number of etio-
activator of nuclear factor-κB ligand (RANKL), also plays an impor- logic factors, including inadequate erythropoietin production caused
tant role in OC growth and differentiation via its receptor located by renal dysfunction, erythropoietin unresponsiveness predominately
on OCs. RANKL is secreted by stromal cells and OBs and induces caused by various cytokines produced by MM cells, dilution resulting
differentiation and maturation of OC progenitors. Osteoprotegerin from a significantly increased immunoglobulin level, and bone
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(OPG) acts as a decoy receptor for RANKL and plays a significant marrow infiltrative processes. Part of the development of anemia
role in the development of bone disease in myeloma. In myeloma, the may also be related to high IL-6 levels. In patients who have had a
soluble syndecan produced by myeloma cells occupies and sequesters number of treatments, quite often anemia is related to repeated
OPG, leading to excess RANKL activity, which induces OC dif- rounds of chemotherapy. Erythropoietin administration therefore is
ferentiation and proliferation with the development of lytic bone an important supportive measure for the symptomatic treatment of
lesions. Importantly, myeloma cells also secrete DKK-1, which has anemia in myeloma. In one study, improvement in hemoglobin was
OB inhibitory activity, leading to suppression of new bone formation observed in 60% of treated patients, and responses were observed in
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and further contributing to bone disease in myeloma. Thus DKK-1 those with low erythropoietin levels compared with normal or high
has become an important therapeutic target to improve bone anabolic levels (72% vs. 20%).
effects. These factors together lead to osteoporosis and lytic bone
lesions. Additionally, direct infiltration of bone by myeloma cells also
causes bone destruction. Overall, one observes pain that is aggravated Neurologic Symptoms
on movement and also collapse of vertebrae leading to a decrease
in height as well as symptoms of nerve compression. Besides pain, Patients with MM present with a number of neurologic symptoms
involvement of extremity and/or spine leads to lack of mobility and related either to direct involvement of the nervous system or the
associated problems, including predisposition to thrombotic events. impact of cytokines and/or paraproteins on the nervous system. The
most common abnormality is compression of the spinal cord and/or
nerve roots giving rise to pain as well as various degrees of neurologic
Hypercalcemia dysfunction, including paraplegia with loss of bladder and bowel
control. Cord compression is considered a neurologic emergency
Hypercalcemia is observed in approximately 25% to 30% of patients requiring prompt intervention, which might allow complete recovery
with myeloma and is usually a manifestation of higher disease burden. of function. In this setting, urgent MRI followed by radiotherapeutic