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1756 Part XI: Malignant Lymphoid Diseases Chapter 107: Myeloma 1757

should be suspected with repeated episodes of VTE. The incidence may be indicated in some patients. A survival benefit for patients who
of VTE is highest during the first 3 to 4 months following diagnosis were anticoagulated for a VTE may suggest an additional effect of anti-
and occurs in approximately 3 to 4 percent of patients receiving either coagulants on the myelomatous process. 543
dexamethasone alone or MP, but is much higher when newer agents
are combined with dexamethasone and melphalan. 271,538,539 A number
of procoagulant abnormalities have been described in myeloma, includ- Peripheral Neuropathy
ing endothelial damage, paraprotein interference with fibrin structure, Bortezomib- 546,547 and thalidomide-induced 548,549 peripheral neuropathy
elevated von Willebrand multimers, elevated factor VIII, decreased pro- should be distinguished from other causes such as paraneoplastic neu-
tein S, and acquired activated protein C resistance. 540,541 A SNP analysis ropathies, antecedent chemotherapy with neurotoxic agents (vincristine
discovered 18 polymorphisms associated with thalidomide-induced or cisplatin), diabetes mellitus, and AL amyloidosis. Patients with AL
VTE. These polymorphisms were involved in pathways important for amyloidosis of the peripheral nerves are especially sensitive to neuro-
drug transport or metabolism, DNA repair, and cytokine pathways. toxic agents. Clinical findings include bilateral tingling, and numbness
542
The precise mechanisms causing VTE in myeloma patients absent a in the toes and/or fingers and/or pain ascending in the extremities
known genetic predisposition remain elusive, but the type of therapy when neurotoxic drug therapy is continued. Symptoms are typically in a
plays an important role. glove-and-stocking distribution. Neurologic examination should evalu-
The incidence of VTE with single-agent thalidomide is approxi- ate sensory loss, deep tendon reflexes, and distal weakness, especially in
mately 2 to 4 percent in newly diagnosed and in relapsed patients, com- the lower extremities. If significant weakness or asymmetry of signs is
parable to that observed with dexamethasone alone or MP, implying present, a neurologic consultation must be obtained along with electro-
that thalidomide alone does not increase the risk of VTE. However, the myography and nerve conduction studies.
risk for VTE increases significantly when thalidomide is combined with Bortezomib inhibits NF-κB activation, blocking the transcription
dexamethasone, melphalan, doxorubicin, or cyclophosphamide, or with of nerve growth factor–mediated neuron survival. Other proposed
multiagent chemotherapy. 274,432 The MPT combination causes VTE in 12 mechanisms for bortezomib-induced neuropathy include mitochondria
to 20 percent of patients who do not receive anticoagulant prophylaxis, and endoplasmic reticulum damage because of activation of the mito-
whereas the incidence of VTE with thalidomide and dexamethasone in chondrial-based apoptotic pathway. 546,550,551 Second-generation, more
newly diagnosed patients is 14 to 26 percent. 271,411,431,538 Most VTEs occur selective proteasome inhibitors such as carfilzomib have a reduced neu-
552
within the first 60 days of therapy, coinciding with maximum cytore- rotoxicity. Grade 3 or 4 bortezomib-induced neurotoxicity occurs in
duction. In the Total Therapy 2 study, 22 percent of patients developed a approximately 20 percent of newly diagnosed patients and in 30 percent
543
VTE, 95 percent of which occurred in the first 12 months of therapy. of patients with relapsing disease. 417,553,554 A 50 percent dose reduction
Oral regimens principally promote deep vein thrombosis or pulmonary should be made for bortezomib-induced grade 2 neuropathy while
embolism, whereas infusional regimens can give rise to central line– grade 3 or 4 neuropathy requires drug discontinuation. Improvement
related thrombosis in approximately 50 percent of patients. 542 or resolution of symptoms has been reported in 3 months, whereas
Single-agent lenalidomide does not appear to increase VTE, in other patients maximum improvement may take 2 years. 403,553,555,556
at least not in the setting of myeloma relapse, but is associated with Subcutaneous dosing of bortezomib appears to be similarly effective
a marked increase in VTE risk when lenalidomide is combined with to intravenous administration and has a significantly improved safety
dexamethasone. Three risk factors for lenalidomide-associated VTE profile. When compared head-to-head, 38 percent of patients receiving
482
are higher dexamethasone doses, administration of erythropoietin, bortezomib subcutaneously reported any grade of neuropathy com-
and concomitant administration of other agents. When combined with pared to 53 percent when given IV (p = 0.044). By grade, 24 percent
cyclophosphamide, the incidence of lenalidomide-induced VTE was 14 versus 41 percent (p = 0.012) had grade 2 or worse, and 6 percent versus
544
percent. Bortezomib did not seem to increase the risk of VTE, at least 16 percent (p = 0.026) had grade 3 or worse when comparing subcu-
557
not in patients with relapsed or refractory disease. 272 taneous with intravenous administration, respectively. Subcutaneous
Prevention of VTE is based on the assessment for known risk fac- administration is now the preferred route of administration based on
tors for VTE: (1) myeloma-related (hyperviscosity, newly diagnosed sta- these findings.
tus); (2) therapy-related (high-dose dexamethasone [≥480 mg/month], Daily thalidomide dose, dose intensity, cumulative dose 400 mg or
doxorubicin, multiagent chemotherapy); (3) individual factors (age, greater, and duration of therapy are all implicated in the pathogenesis
history of VTE, inherited thrombophilia, obesity, immobilization, cen- of thalidomide-induced neuropathy, which occurs in up to 75 percent
tral venous line, infections, surgery, administration of erythropoietin); of patients. 548,549,558–563 Dose reduction or cessation of therapy with the
and (4) factors related to comorbidities (acute infection, diabetes mel- option of switching to lenalidomide will usually improve neuropathy,
litus, cardiac or renal dysfunction). Therapy-related risk factors weigh although resolution or improvement of neuropathy can take consider-
highest in the risk equation for VTE. The following thromboprophy- able time as thalidomide appears to induce an axonal-length-dependent
564
laxis is recommended: (1) acetylsalicylic acid (aspirin) in either a stan- neuropathy. Symptomatic treatment for thalidomide- and borte-
dard dose of 325 mg/day or in a low dose of 81 mg/day for patients with zomib-induced neuropathy usually comprises gabapentin, pregabalin,
one or no risk factors or (2) low-molecular-weight heparin (LMWH) or tricyclic antidepressants.
once a day, or full-dose warfarin for patients if two or more risk factors
or therapy-related risks are present. The recommended duration of pro- Osteonecrosis of the Jaw
phylaxis in general is 6 to 12 months. 432 ONJ is a severe “bone” disease, associated with bisphosphonate ther-
Therapy for VTE should begin with standard therapeutic doses apy that affects the jaws and typically presents as infection with necrotic
of LMWH. Oral anticoagulation may be considered as a followup. If bone in the mandible or maxilla. ONJ is characterized by the presence
oral anticoagulation is deemed inappropriate in a given patient, LMWH of exposed bone in the maxillofacial region that does not heal within 8
should be continued as long as the patient is receiving antineoplastic weeks. Although asymptomatic at times, ONJ usually presents as pain
therapy. The optimal duration of therapy is unknown but one study and/or numbness in the affected area, soft-tissue swelling, drainage, and
reported a recurrence of VTE of 10 percent in patients who had discon- tooth mobility. The exact cause of ONJ is not known and is likely to be
545
tinued anticoagulant therapy, suggesting that long-term prophylaxis multifactorial. The risk of developing ONJ increases with duration of

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