Other Adverse Events
Thalidomide and lenalidomide. When used alone, neither lenalidomide nor thalidomide(Drug information on thalidomide) increases the risk of venous thromboembolic events (VTEs), but the risk increases substantially when these agents are used in conjunction with dexamethasone(Drug information on dexamethasone) or chemotherapy. In a phase III trial, the incidence of grade 3/4 deep venous thrombosis and pulmonary embolism was 14.7% in the lenalidomide + dexamethasone group compared with 3.4% in the placebo + dexamethasone group.[4,5,8] Regimens combining immunomodulatory drugs with doxorubicin(Drug information on doxorubicin) are associated with a 4.3-fold increase in VTEs.
Bortezomib. In contrast, in a phase I/II dose-escalation study of the combination of bortezomib(Drug information on bortezomib) + lenalidomide + dexamethasone for the treatment of newly diagnosed R/R MM, the incidence of VTE was substantially lower than that in a similar Eastern Cooperative Oncology Group trial of lenalidomide + dexamethasone.[52,53] This suggests that bortezomib dampens or nullifies the VTE-promoting effects of immunomodulatory drugs. A review of phase III studies evaluating various combination therapies with or without bortezomib also revealed a reduced rate of VTEs in those combinations incorporating bortezomib.
Pomalidomide. Preliminary data on the combination of pomalidomide and dexamethasone indicate risk for VTEs. In one trial, the incidence of thrombosis was reported as < 5%, while in another study VTEs occurred in 4 of 38 patients treated with pomalidomide ± dexamethasone, despite the use of low-dose aspirin(Drug information on aspirin) as thromboprophylaxis.
Carfilzomib. The incidence of VTEs in phase II studies of carfilzomib has been low—< 2% in one trial and < 5% in a second trial in a patient population that had significant prior exposure to thalidomide and lenalidomide.
Management. Thromboembolic events are serious and potentially life-threatening and can result in complications that permanently affect the lives of patients and their families. Indeed, the National Comprehensive Cancer Network (NCCN) recommends prophylactic anticoagulation therapy in conjunction with lenalidomide/dexamethasone combination therapy and thalidomide-based therapies. The International Myeloma Working Group recommends that VTE prophylaxis be tailored according to the presence of individual, disease-related, and treatment-related risk factors (Table 7) and may include low–molecular weight heparin(Drug information on heparin) (LMWH) or aspirin, among other interventions.[6,51,56] A recently published phase III, open-label, randomized study of 667 patients with previously untreated MM showed that aspirin and warfarin(Drug information on warfarin) were similarly effective compared with LMWH in reducing serious VTEs, acute cardiovascular events, and sudden deaths in patients treated with thalidomide-based regimens. However, in elderly patients warfarin showed less efficacy than LMWH.
Gastrointestinal adverse events
Thalidomide and lenalidomide. Constipation is the most common gastrointestinal AE associated with thalidomide, whereas both constipation and diarrhea can occur with lenalidomide. In phase II studies of thalidomide in patients with R/R MM, grade 1/2 constipation occurred in 40% of patients, and grade 3/4 constipation occurred in 16% of patients. Constipation and diarrhea were common in phase III studies with lenalidomide/dexamethasone combination therapy,[4,5] affecting 31% and 36% of patients, respectively, although grade 3/4 constipation, diarrhea, and nausea occurred in < 4% of patients.[4,5]
Bortezomib. Gastrointestinal AEs were also common in the phase III APEX trial of bortezomib in patients with R/R MM. Diarrhea, constipation, nausea, and vomiting occurred in 35% to 57% of patients, with grade 3/4 diarrhea occurring in 7% of patients, and grade 3/4 constipation or nausea/vomiting occurring in 2% to 3% of patients.
Pomalidomide. Limited data are currently available on the incidence of gastrointestinal AEs related to treatment with pomalidomide. In one study of pomalidomide ± dexamethasone, diarrhea was reported as a pomalidomide-related serious AE.
Carfilzomib. The incidence of gastrointestinal AEs in trials of carfilzomib has been on the order of 36% to 54% for nausea, 24% to 36% for diarrhea, and 12% to 25% for constipation and vomiting, although most of these events have been grade 1/2 in severity.[20,21,38] The incidence of grade 3 gastrointestinal AEs in carfilzomib studies has been in the range of 1% to 2%.
Management. Management plans for gastrointestinal toxicities typically include dietary changes, medications (stool softeners, osmotic laxatives, antidiarrheals, antiemetics), and fluid/electrolyte management, along with rigorous perineal and oral care. Hypnosis, relaxation techniques, and acupuncture may also be beneficial. Dose reduction is recommended in the event of severe gastrointestinal reactions.[6,59]
Thalidomide and lenalidomide. One recent study involving 202 patients treated with thalidomide-containing regimens found that severe infections developed in 19% of patients early during the course of induction therapy; most of the infections were pneumonia. Although grade 3/4 febrile neutropenia was not a common occurrence in patients receiving lenalidomide in phase III studies, grade 3/4 infections were reported in approximately 10% to 22% of patients receiving the lenalidomide/dexamethasone combination, compared with 6% to 12% in those receiving dexamethasone alone.[4,5,8]
Bortezomib. The risk of herpes zoster infection has been shown to increase with bortezomib therapy, and acyclovir prophylaxis is recommended for all patients receiving bortezomib-based therapy.[1,6] In the phase III APEX trial of bortezomib monotherapy vs dexamethasone in patients with R/R MM, herpes zoster was more common in the bortezomib group than in the dexamethasone group (13% vs 5%, respectively). Pyrexia was reported in 35% of patients treated with bortezomib compared with 16% of patients receiving dexamethasone.
Pomalidomide. Little information is available regarding the incidence of infections associated with pomalidomide therapy. Infection was reported as a serious AE in the phase I study of pomalidomide ± dexamethasone.
Carfilzomib. The most common type of infection observed in clinical studies of carfilzomib was pneumonia. In the two major phase II studies, pneumonia occurred at rates of 9.8% and 13.9%.[20,21] Most of these events were grade 3 in severity.
Management. In patients with R/R MM, more than 90% of infections are caused by gram-negative bacteria or Staphylococcus aureus. When the risk of infection is increased, as in patients receiving high-dose dexamethasone, elderly patients, and those with certain comorbidities, routine antibiotic prophylaxis may be appropriate. Patients being treated with bortezomib should receive herpes prophylaxis. Generally speaking, the vaccination/immunization status of all patients with MM should be optimized.
Thalidomide and lenalidomide. Some degree of sedation is expected with thalidomide; patients may also experience fatigue, weakness, inability to concentrate, or mood alterations.[3,28] In phase II trials of thalidomide in patients with R/R MM, grade 1/2 somnolence occurred in 43% of patients, and grade 3/4 somnolence in 11% of patients. Grade 3/4 fatigue was reported in approximately 6% to 7% of patients treated with lenalidomide + dexamethasone in phase III studies.[4,5]
Bortezomib. Fatigue (of any grade) was reported in 42% of bortezomib recipients and in 32% of dexamethasone recipients in the phase III APEX study, but grade 3/4 fatigue was relatively infrequent (< 5%). Pyrexia (> 38ºC) was also reported as an AE for 22% of patients treated with bortezomib in one phase II study and for 35% of patients in another study. The pyrexia was grade 3 in only 2% to 4% of patients.
Pomalidomide. Grade 1/2 fatigue was reported as the most common nonhematologic toxicity in one study of pomalidomide + low-dose dexamethasone. The incidence was 43% in patients treated with 2 mg of pomalidomide daily and 52% in patients treated with 4 mg daily.
Carfilzomib. Fatigue was the most common nonhematologic toxicity reported in phase II clinical studies of carfilzomib. The incidence was 46% in one study and between 54% and 71% in a second study. Most of these events were grade 1/2 in severity.
Management. Patients with R/R MM who present with fatigue should be evaluated for possible causes and provided with recommendations for proper hydration, nutrition, dietary supplements, and lifestyle changes, as well as antidepressants or counseling as appropriate. Patients should be instructed to avoid situations where drowsiness may be a problem, and they should not take other medications that may cause drowsiness without adequate medical advice.
Dermatologic adverse events
Thalidomide and lenalidomide. In phase II trials of thalidomide in patients with R/R MM, grade 1/2 dermatologic AEs occurred in 15% of patients, and grade 3/4 AEs occurred in approximately 3%. Thalidomide-induced dermatologic toxicity commonly presents as a pruritic maculopapular rash starting on the trunk and extending to the back and proximal limbs. Similar rates have been reported with lenalidomide-based regimens, with rash occurring in approximately 16% of patients treated with lenalidomide + dexamethasone. Angioedema and serious dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients receiving both lenalidomide and thalidomide.[8,42] TEN may be associated with mortality rates greater than 30%.
Bortezomib. Grade 3/4 dermatologic toxicity is rare with bortezomib-based regimens. Rash (all grades) occurred in 18% of bortezomib recipients vs 6% of dexamethasone recipients in the phase III APEX study, but only 1% of bortezomib recipients experienced grade 3 dermatologic toxicity. Bortezomib-induced dermatologic toxicity is characterized by a maculopapular or nodular rash on the back, trunk, and face, which usually resolves with a combination of systemic corticosteroids and antihistamines. Cases of bortezomib-induced lupus erythematosus tumidus have also been reported.
Pomalidomide. There are no data currently available on the incidence of dermatologic AEs related to treatment with pomalidomide.
Carfilzomib. Dermatologic AEs have been relatively infrequent with carfilzomib in phase II studies in patients with R/R MM. The most common dermatologic AE was rash, occurring in 6.8% and 10.2% of patients in each of the two trials.[20,21] Most events were grade 1/2 in severity.
Management. Temporary discontinuation of thalidomide and lenalidomide generally leads to resolution of mild rashes. If the rash is exfoliative, purpuric, or bullous, or if SJS or TEN is suspected, the immunomodulatory agent should not be resumed. Patients with a history of grade 4 rash associated with thalidomide treatment should not receive lenalidomide.