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Complications of Multiple Myeloma Therapy, Part 2: Risk Reduction and Management of Venous Thromboembolism, Osteonecrosis of the Jaw, Renal Complications, and Anemia

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Complications of Multiple Myeloma Therapy, Part 2: Risk Reduction and Management of Venous Thromboembolism, Osteonecrosis of the Jaw, Renal Complications, and Anemia S-13 Supplement Complications of Multiple Myeloma Therapy, Part 2: Risk Reduction and Management of Venous Thromboembolism, Osteonecrosis of the Jaw, Renal Complications, and Anemia Ruben Niesvizky, MD,a and Ashraf Z. Badros, MD,b New York, New York, and Baltimore, Maryland Key Words and improved duration of response, but they have been Thalidomide, bortezomib, lenalidomide, deep vein thrombosis, associated with an increased risk of certain adverse pulmonary embolism, bisphosphonates, erythropoiesis- events. Venous thromboembolism (VTE), osteonecro- stimulating agents sis of the jaw (ONJ), renal failure, and anemia are all common complications of MM therapy. Community Abstract Venous thromboembolism (VTE), osteonecrosis of the jaw, renal fail- oncologists should be familiar with these potential com- ure, and anemia are all common complications of multiple myeloma plications and the strategies for preventing, identifying, therapy. Many of these adverse events have been documented only and managing them. in the past 5 to 10 years, in conjunction with the introduction of a series of the newer therapies thalidomide, bortezomib, and lenalid- omide. This article discusses these complications in detail and pro- Venous Thromboembolism vides strategies for health care providers to best prevent, identify, and manage them. Preventive measures, such as VTE prophylaxis VTE typically manifests as deep vein thrombosis (DVT) and appropriate dental hygiene, as well as patient education, dose or pulmonary embolism (PE). Both cancer and cancer adjustments, limited duration of drug treatment, and consideration treatments have been identified as discrete risk fac- of therapies that are associated with less burdensome adverse-event tors.1 Current evidence indicates that cancer increases profiles, can contribute to substantially improved outcomes and thrombosis risk 4.1-fold and chemotherapy increases quality of life. (JNCCN 2010;8[Suppl 1]:S13–S20) the risk 6.5-fold.2 Other key VTE risk factors include older age, recent surgery, acute medical illness, and im- Therapies such as thalidomide, bortezomib, and le- mobility or bed rest. The risk of VTE is typically cumu- 1 nalidomide have provided meaningful benefits in mul- lative. Therefore, even if an independent relationship tiple myeloma (MM), such as improved response rates between VTE and specific cancers such as MM were excluded, the advanced age of most MM patients and other factors common in MM patients would tend to 3 From aWeill Cornell Medical College, New York, New York, and place them at heightened VTE risk. A recent, retro- bUniversity of Maryland, Greenebaum Cancer Center, Baltimore, Maryland. spective analysis of a managed care database of patients Dr. Niesvizky has disclosed that he has participated as an advisory with MM (N = 1732) showed that 66.3% had at least board member, speakers’ bureau member, or consultant for 4 Celgene Corp.; Millennium Pharmaceuticals, Inc.; and Proteolix, 1 VTE risk factor and 48.3% had at least 2 risk factors. Inc. Dr. Badros has no interest, arrangement, or affiliation with It has been posited that the hypercoagulable state the manufacturers of any products discussed in the article or their competitors. typical with MM and other cancers provides a pro- This work was supported by an educational grant from Millennium thrombotic baseline environment. The prothrombotic Pharmaceuticals, Inc. Correspondence: Ruben Niesvizky, MD, Weill Cornell Medical state associated with MM may be due to multiple hemo- College, 520 East 70th Street, Starr 341, New York, NY 10021. static abnormalities, including activation of coagulation E-mail: [email protected] pathways, reduced natural anticoagulation mechanisms, © Journal of the National Comprehensive Cancer Network | Volume 8 Supplement 1 | February 2010 S-14 Supplement Niesvizky and Badros and an inflammatory milieu.5–8 Acquired resistance is administered as a single agent.16,17 However, stud- to activated protein C is a common coagulation ab- ies have shown elevated VTE risk ranging from 8.5% normality in MM, and it has also been associated to 15.0% when lenalidomide is combined with dexa- with increased thromboembolism risk.5 Conditions methasone.8,14,18,19 More recent trials have shown that result in hypercoagulable states include immu- that lowering the dexamethasone dosage reduces the noglobulin interference with fibrin structure and risk of VTE with lenalidomide substantially.20,21 paraprotein acting as an autoantibody against in- Heightened VTE risk has also been associ- trinsic anticoagulants and phospholipids.9–11 A small ated with the use of erythropoiesis-stimulating recent study (N = 49) of patients with MM receiving agents (ESAs), such as epoetin alfa and darbepo- thalidomide confirmed that most patients who sub- etin alfa.12 Anemia is discussed in more detail in sequently experienced a thrombotic episode had an subsequent sections. 7 underlying hypercoagulability abnormality. Bortezomib Underlying VTE risk often escalates with thera- The proteasome inhibitor bortezomib does not ap- peutic intervention and is typically greatest after pear to increase VTE risk; in fact, it may exert anti- initial therapy. For example, approximately half of thrombotic actions. Proteasome inhibition is known VTE events in patients with MM occur within 2 to decrease expression of endothelial and vascular 5 months of treatment initiation. Varying risk levels cell adhesion molecules; in addition, bortezomib are associated with specific therapies and therapeutic has been shown to inhibit adenosine diphosphate– combinations. In particular, VTE rates are high in induced platelet aggregation.22 Two phase III studies patients receiving the immunomodulatory drugs tha- indicate that bortezomib is associated with throm- lidomide or lenalidomide in combination with high- bocytopenia rates ranging from 20% to 26% (grade dose dexamethasone, doxorubicin, or combination 3) and 4% to 17% (grade 4), but a very low (1%) 12 chemotherapy. Dexamethasone alone has also been VTE rate.23,24 shown to somewhat increase thrombosis risk.8,13,14 Treatment and Prophylaxis Recommendations Thalidomide Current VTE prophylaxis guidelines from the A recent systematic review and meta-analysis of 17 American College of Chest Physicians (ACCP) randomized, controlled trials found an overall VTE recommend primary antithrombotic prophylaxis for incidence of 11.7% in thalidomide-treated patients patients with cancer only if they are bedridden or 15 (95% CI, 8.1%–16.5%). This finding should be undergoing surgical intervention.1 However, as dis- considered in the context of a systemic review by cussed previously, without prophylaxis, the risk for 5 Zangari et al., who assessed relapsed/refractory ver- VTE in treated MM patients is unacceptably high. sus newly diagnosed MM, as well as thalidomide In addition, PE is associated with a high case-fa- monotherapy versus combination therapy, and found tality rate. One-week survival after PE is 71%, but wide variation in VTE risk. Studies of thalidomide one-quarter of all cases present as sudden death.25 monotherapy showed VTE rates of less than 2% to Therefore, identifying high-risk patients and provid- 4% in both newly diagnosed patients and those with ing them with appropriate prophylaxis is essential. relapsed/refractory disease. Newly diagnosed patients Unfortunately, very few randomized studies have receiving combination therapy had rates ranging assessed the impact of anticoagulant prophylaxis in from 17% to 28%. The rates of VTE in patients with patients with cancer. relapsed/refractory MM who received combination The International Myeloma Working Group thalidomide therapy tended to be lower (8% to 21%) (IMWG) recently published guidelines for prevent- but were still a cause for concern. The combination ing VTE in myeloma.12 Primary data were lacking regimens evaluated included thalidomide/dexameth- in many cases, so the IMWG recommendations are asone, thalidomide/melphalan/prednisone, and tha- based on expert assessment or data extrapolation lidomide plus conventional chemotherapy. from studies not designed specifically to assess pro- Lenalidomide phylaxis efficacy or safety. Therefore, they should As with thalidomide, the risk for VTE with lenalido- not override the treating physician’s best judgment. mide is low, ranging from 0% to less than 5%, when it Because VTE risk is frequently cumulative, patients © Journal of the National Comprehensive Cancer Network | Volume 8 Supplement 1 | February 2010 Supplement S-15 Complications of Multiple Myeloma Therapy may present with a combination of disease-related Table 1 Risk Factors to Consider When and individual risk factors, as well as inherited and Screening Multiple Myeloma Patients non-inherited risk factors. All of these must be for Thromboprophylaxis considered alongside therapeutically mediated risk. Individual Factors Table 1 lists risk factors and related screening con- General patient characteristics 2,12,26 siderations for MM patients. • Age According to the IMWG, selection of candidates • Obesity and/or diabetes for thromboprophylaxis should be based on the base- • Cardiovascular or renal disease line VTE risk associated with each therapy.12 The • Acute infection IMWG recommends reducing VTE risk to less than 10% using the safest and least cumbersome prophy- Inherited thrombophilic abnormalities laxis available. High-dose dexamethasone adminis- • Antithrombin III deficiencies tration is considered an independent risk factor for • Protein C and protein
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