Expanding Role of Bortezomib in Multiple Myeloma: Nursing Implications

Kathleen Colson, RN, BSN, BS; Deborah S. Doss, RN, OCN; Regina Swift, RN, BSN; Joseph Tariman, RN, APN, MN, BC, OCN

Disclosures

Cancer Nurs. 2008;31(3):239-249. 

In This Article

Management of Side Effects

It is important that patients know the likely side effects of their therapy; thus, nurses should educate patients and caregivers and encourage reporting of side effects to their doctor, nurse, or other healthcare team members. The most common adverse events in the APEX trial were diarrhea, nausea, fatigue, constipation, and peripheral neuropathy ( Table 4 ). The most common grade 3 or 4 adverse events were thrombocytopenia, neutropenia, and anemia. These findings are consistent with the safety profile determined in SUMMIT and CREST.[10,12] In the SUMMIT and CREST extension study, there were no new cumulative toxicities during prolonged bortezomib therapy,[21] and retreatment or continuation of bortezomib treatment beyond 6 months was well tolerated.

Results of additional studies in Europe are consistent with this safety profile. In a Netherlands community practice study, most adverse events were low grade.[13] In a small study of bortezomib plus dexamethasone conducted in Germany, the most common side effects were myelosuppression, neuropathy, and fatigue, all of which were manageable.[14] Thrombocytopenia, anemia, neuropathy, and gastrointestinal events were most common in a study of bortezomib in the Czech Republic.[15] Interestingly, in a Korean retrospective analysis, the incidence of thrombocytopenia and neurotoxicity was similar to that seen in Western studies, but gastrointestinal toxicities were relatively infrequent.[30] Measures that can be taken to reduce the risk of side effects or lessen their severity are summarized in Table 5 and discussed below.

In the APEX trial, most gastrointestinal effects (diarrhea, nausea, constipation, and vomiting) were mild or moderate ( Table 4 ) and occurred during the first or second cycle of treatment.[8] Interventions for each of these effects are shown in Table 5 .

The onset of fatigue typically occurs in the first or second cycle of treatment.[31] Most patients are able to continue therapy despite fatigue.

Bortezomib treatment can be associated with peripheral neuropathy that is predominantly sensory, characterized by pain, paresthesia, burning dysesthesia, and numbness. Some cases of motor neuropathy have also been reported.[20,31] It is essential that patients immediately report any tingling, numbness, pain, or burning sensation in their hands, arms, feet, or legs. Feet are more typically affected than hands.[31] If necessary, the dose can be modified or treatment interrupted ( Table 3 ) until symptoms resolve. A useful tool in detecting peripheral neuropathy is the neurotoxicity assessment tool shown in Figure 2. This can be completed at every clinic visit and helps to emphasize the importance of patient vigilance, increases awareness of symptoms, and provides a framework for tracking changes in symptoms. An analysis of combined data from SUMMIT and CREST demonstrated that before receiving bortezomib, 81% of patients showed evidence of peripheral neuropathy according to the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity questionnaire.[22] Furthermore, symptoms of peripheral neuropathy are a feature of MM and are often under-recognized; in a population of untreated patients with MM, one-half showed evidence of peripheral neuropathy by neurophysiologic examination.[32]

Neurotoxicity Assessment Tool. Based on the functional assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity questionnaire (http://www.facit.org/qview/qlist.aspx) and the National Cancer Institute Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events Version 3.0 (http://ctep.cancer.gov/reporting/ctc_v30.html).

In the APEX trial, peripheral neuropathy generally emerged by treatment cycle 5, with the prevalence subsequently reaching a plateau. In total, 27% of patients experienced grade ≥ 2 treatment-emergent peripheral neuropathy, of whom 55% had complete resolution to baseline and a further 9% experienced improvement by at least 1 severity rade.[33] The median time to resolution or improvement from initial diagnosis of peripheral neuropathy was 110 days. The dose modification schema in Table 3 was used in the APEX trial, and it seemed that a higher proportion of patients with peripheral neuropathy who followed these recommendations experienced resolution or improvement (68%), compared with those who did not undergo dose modification for their peripheral neuropathy (47%).[33] The characteristics of peripheral neuropathy in SUMMIT and CREST were similar to those seen in APEX.[22] Prevalence of peripheral neuropathy reached a plateau at cycle 5 of treatment, remaining consistent through cycle 8. Among the 14% of patients with clinically significant neuropathy (grade = 3 and/or requiring discontinuation), 71% experienced resolution to baseline or improvement based on the data at last follow-up, including 37% who resolved/improved during treatment and 31% who resolved/improved after treatment. (The timing of improvement was unclear in 1 patient.) The median time to resolution or improvement from the last dose of bortezomib was 47 days.[22]

The course of bortezomib-associated thrombocytopenia is typically transient and cyclical, recovering toward baseline during the rest period of each cycle.[34] This pattern of reversibility continues during long-term treatment.[21] Bortezomib may induce thrombocytopenia via a reversible effect on megakaryocytic platelet production, possibly by inhibiting platelet budding, rather than a direct cytotoxic effect.[35]

Based on data from SUMMIT and CREST,[35] patients with a low (<70 × 109/L) baseline platelet count, high baseline M-protein concentration, and a higher number of prior therapies are at increased risk of developing grade 3 or 4 thrombocytopenia. Therefore, platelet counts should be monitored continuously in these patients.[31] Patients receiving concomitant anticoagulants, nonsteroidal antiinflammatory drugs, or thrombolytics may be at increased risk of bleeding and so require careful monitoring. However, no differences in significant bleeding events (including grade ≥3 bleeding events) were observed between patients treated with bortezomib and dexamethasone in the large phase 3 APEX trial.[34]

Given the well-characterized, manageable, and reversible nature of thrombocytopenia with bortezomib, platelet transfusion support rather than dose reduction, particularly in the first 2 cycles, may be warranted when clinically indicated to maximize the benefit of bortezomib.[35]

In the APEX trial, bortezomib-associated neutropenia was transient and cyclical,[34] and only 6% of patients required granulocyte-colony-stimulating factor. Febrile neutropenia was rare.

In the SUMMIT, CREST, and APEX studies, 11% to 12% of patients experienced hypotension, notably postural or orthostatic hypotension. These events were observed throughout therapy with bortezomib and were mostly mild or moderate.[20] Management of orthostatic/postural hypotension includes adjustment of antihypertensive medications, hydration, and administration of mineral corticoids and/or sympathomimetics.

Between 15% and 21% of patients in the SUMMIT, CREST, and APEX studies experienced a rash, which was generally mild or moderate in severity.[8,10,12] Diphenhydramine or hydrocortisone creams can be administered to patients with a rash; low-dose prednisone may alleviate hives. If the rash improves or resolves, patients can continue treatment. In patients with non-Hodgkin lymphoma, a possible relationship between rash and treatment response has been reported,[36] and bortezomib use can be continued in patients with careful monitoring.

Herpes zoster infection has been reported with bortezomib: 13% of patients in the APEX trial and 12% in the Netherlands community practice study.[13,37] In some centers, acyclovir is administered prophylactically with bortezomib combination therapy; in others, prophylaxis is given only to patients with a history of infections.[31] No prospective studies have evaluated the effects of antiviral prophylaxis.

No formal drug interaction studies have been conducted, but patients receiving medications that can cause myelosuppression (such as melphalan) should be monitored closely.[38] The enzyme CYP3A4 is important in the hepatic metabolism of bortezomib.[20] Therefore, patients receiving bortezomib concomitantly with CYP3A4 inhibitors (such as amiodarone, cimetidine, grapefruit juice, azoles, and erythromycin) or inducers (such as barbiturates and carbamazepine) should be monitored closely for toxicities and/or reduced efficacy.[20,38] Bortezomib-induced severe recurrent hepatitis that requires discontinuation of bortezomib has been reported.[39] Patients taking oral antidiabetic drugs may require dose adjustment of their antidiabetic medication while receiving bortezomib; during clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics.[20,38]

Bortezomib is contraindicated in patients with hypersensitivity to boron or mannitol[20,38] and should be administered with caution to patients with preexisting fluid retention.[40] Patients with preexisting heart disease or risk factors for heart disease should be monitored closely. Patients with a high tumor burden require monitoring and, if appropriate, precautions such as adequate hydration and allopurinol treatment should be taken for tumor lysis syndrome.[31]

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