Management of Single-Agent Carfilzomib Adverse Events in Patients with Relapsed or Refractory Multiple Myeloma: Applying the Lessons from Clinical Trials to Clinical Practice

Introduction
The American Cancer Society estimates that 24,050 new cases of multiple myeloma (MM) will be diagnosed in the United States in 2014 and that MM will cause approximately 11,090 deaths.1 The 5-year survival rate, by year of diagnosis, for people with MM has improved in recent decades in the United States (1985-1989, 27.4%; 1995, 33.4%; 2005, 44.9%2), and several treatment options are currently available. Nevertheless, MM remains incurable and patients who become refractory to treatment have a poor prognosis, with a median event-free survival and overall survival (OS) of 5 and 9 months, respectively.3 Existing agents, including the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, have improved outcomes and OS rates in patients with relapsed and refractory MM (RRMM).4-6 However, there is a lack of adequate treatment for patients who have failed these agents, suggesting that treatments with greater efficacy and improved safety profiles are needed, especially for patients with advanced disease.3 In this regard, carfilzomib, a selective proteasome inhibitor, received approval in 2012 by the US Food and Drug Administration (FDA) for RRMM based on the efficacy results from a single-arm trial (PX-171-003-A1)7,8 and the combined safety data from 4 phase 2 studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005).8
A complicating factor in the treatment of RRMM is the fact that MM usually occurs in older patients (75%-79% are >70 years of age) such that they generally have a number of coexisting comorbidities.9 For example, approximately two-thirds of patients with MM have baseline cardiovascular risk factors (eg, hypertension, diabetes, hyperlipidemia, coronary artery disease, congestive heart failure) or a history of an acute cardiac event,4,10 and up to 50% of patients with MM have renal dysfunction.11,12 Hematologic complications also commonly arise in MM, and 70% or more of patients with MM are anemic at the time of diagnosis.13,14 Moreover, myelosuppression in these patients can lead to diminished levels of serum immunoglobulins and increased incidences of infections, including upper respiratory tract infections and pneumonia.1,15,16

Thus, an understanding of the adverse events (AEs) associated with carfilzomib treatment is important in order to individualize its use for patients, based on their specific clinical characteristics. This review summarizes the safety profile of single-agent carfilzomib in RRMM, and provides practical recommendations for the clinical management of potential AEs associated with carfilzomib use.

Appropriate Use of Single-Agent Carfilzomib in RRMM
Carfilzomib is approved in the United States for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an IMiD, and have demonstrated disease progression within 60 days of completion of the last therapy.8 Intravenous (IV) carfilzomib should be administered over 2 to 10 minutes on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The recommended dose for cycle 1 is 20 mg/m2, with a target dose of 27 mg/m2 in cycle 2 and subsequent cycles if treatment is tolerated. Treatment may continue until disease progression or unacceptable toxicity occurs. During cycle 1, patients should receive IV hydration before administration of each dose of carfilzomib and following administration as needed. In subsequent cycles, IV hydration should be given as needed, and patients should be premedicated with very low-dose dexamethasone (4 mg), oral or IV, prior to all cycle 1 doses, during the first cycle of dose escalation, and if infusion reactions develop or reappear.8

Table 1

Treatment-Related AEs Associated with Single-Agent Carfilzomib: Experience from Pivotal Phase 2 Clinical Trials
The integrated safety profile of single-agent carfilzomib in 526 patients with RRMM in the 4 phase 2 clinical trials upon which FDA approval was based included a total of 278 patients (53%) who received the labeled-dose regimen of 20/27 mg/m2; patients in these trials were heavily pretreated, with a median of 4 prior regimens.17

Overall, patients received a median of 4 cycles of carfilzomib (range, 1-21 cycles) and 19% of patients received 12 cycles.17 Almost all patients experienced a treatment-emergent AE (Table 1); the most frequently reported nonhematologic AEs included fatigue (56%), nausea (45%), dyspnea (35%), diarrhea (33%), and pyrexia (30%). Grade 3 or 4 nonhematologic AEs were uncommon (<10% grade 3 and <1% grade 4), with pneumonia as the most common grade 3 or 4 nonhematologic AE (11%). Of the patients that were treated at 20/27 mg/m2, fewer than 10% required a dose reduction, and 18% of patients completed ≥12 cycles and are participating in an ongoing phase 2 study (PX-171-010) to monitor long-term safety. No evidence of cumulative toxicity was seen in these heavily pretreated patients with RRMM. Of the 526 patients included in the analysis, only 15% required a dose reduction and 23% required a dose delay due to an AE. Among patients who discontinued, 15% discontinued treatment as a result of an AE.17

Hematologic AEs. The most common grade ≥3 AEs were primarily hematologic, including thrombocyto­penia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). Drug discontinuations and dose reductions due to hematologic AEs were rare (≤1.1% for thrombocytopenia, lymphopenia, neutropenia, or anemia).17 Moreover, hematologic AEs following single- agent carfilzomib treatment occurred at similar or lower rates compared with those reported with other agents such as bortezomib, lenalidomide, or pomalidomide.9,17-20

Platelet counts typically decreased during a carfilzomib dosing cycle and returned to baseline by day 1 of the next cycle, with no indication of cumulative or grade 4 thrombocytopenia.17 Neutrophil counts also decreased following carfilzomib treatment and rebounded in a cyclic fashion.21

Febrile neutropenia with carfilzomib therapy was uncommon (reported in 1.1% of treated patients),17 and only 4% of patients with normal neutrophil counts at baseline developed grade 3 or 4 neutropenia. Approximately 50% of the patients in the integrated safety analysis experienced anemia.17 Grade 3 or 4 anemia was reported in 22% of patients; however, no patient with normal hemoglobin at baseline developed grade 3 or 4 anemia while on treatment.

Commentary by Tiffany Richards, MS, ANP, AOCNP: Grade 3 or 4 thrombocytopenia occurred in less than a quarter of patients and few patients required dose modifications. Similar to bortezomib, carfilzomib may cause a cyclical decrease in platelet count, with platelets reaching a nadir around day 8 and recovering by day 1 of the next cycle. While neutropenia occurred in 22.6% of patients, febrile neutropenia occurred in only 1.1% of patients. However, in the integrated analysis, 11% of patients developed pneumonia; 30% of patients developed pyrexia.17

Cardiac/Pulmonary AEs. Although 74% of RRMM patients in the integrated safety analysis had a history of a past cardiac event and 70% had cardiac risk factors at baseline, only 22% of patients reported a grade 1 or higher cardiac event of any type during single-agent carfilzomib therapy, a rate similar to that reported for other MM therapies.17,22,23 In aggregate, congestive heart failure, pulmonary edema, and decreased ejection fraction were reported in 7% of patients.8,24 Interestingly, the mortality rate was the same (7%) in patients treated with carfilzomib who had baseline cardiac risk factors as it was for treated patients without these risk factors.17 However, patients with New York Heart Association (NYHA) Class III–IV heart failure or a history of a recent myocardial infarction/unstable angina were excluded from the phase 2 studies. Nevertheless, carfilzomib is not contraindicated in this patient population although they may be at higher risk for developing treatment-related heart failure or other cardiovascular events.8

Dyspnea was reported in 42% of patients on carfilzomib. However, most incidences were grade 1 or 2 and transient, generally resolving without dose reduction or drug discontinuation.17 In addition, it is difficult to attrib­ute these pulmonary events strictly to carfilzomib therapy because dyspnea is a common complication of the disease itself.

Commentary by Tiffany Richards, MS, ANP, AOCNP: Because most patients are diagnosed with MM later in life, the risk of having preexisting cardiac risk factors is higher in this patient population. Hypertension developed in 14% of patients with half of those patients having a prior history of hypertension. In those patients who developed a cardiac event while on carfilzomib, only 4.4% required discontinuation of treatment. Reasons for treatment discontinuation included congestive heart failure, cardiac arrest, and myocardial infarction.17

Dypsnea was noted in 42% of patients while on carfilz­omib and consisted mostly of grade 1 and 2 events, with only 4.8% of patients having grade 3 dyspnea. The majority of patients (67.9%) experienced recovery of their dyspnea to baseline.17

Renal AEs. Approximately 24% of patients had moderate to severe renal dysfunction (defined as creatinine clearance [CrCl] <50 mL/min) and 39% had mild renal dysfunction (defined as CrCl ≥50 to <80 mL/min) at baseline in the population included in the integrated safety profile. Despite this, AEs of grade 3 or 4 acute renal failure during carfilzomib treatment were rare, and 87% of evaluable patients did not have worsening of renal function while receiving single-agent carfilzomib.17 Among patients who reported any renal event, 50% required no change in carfilzomib treatment, 24% required missed doses, 11% required dose reduction, 3% had delayed doses, and the remaining 12% discontinued treatment.

While 3 of the studies included in the integrated safety analysis limited enrollment to patients with serum creatinine <2 mg/dL and an estimated glomerular filtration rate ≥30 mL/min, the PX-171-005 study specifically examined the use of carfilzomib in patients with varying degrees of renal function (ranging from normal renal function to those requiring chronic dialysis). There were no differences in tolerability or pharmacokinetics of carfilzomib among patients with varying levels of renal impairment in this study, indicating that dose modifications are not needed in patients with renal dysfunction, even in patients on dialysis.25 Indeed, in these patients, carfilzomib was escalated to the target dose (27 mg/m2) that is used in patients with normal renal function (those with an estimated glomerular filtration rate ≥30 mL/min) with no increase in renal AEs.25

Commentary by Tiffany Richards, MS, ANP, AOCNP: In an early clinical trial, a significant percentage of patients developed a rise in their serum creatinine levels after receiving carfilzomib. The study was amended and patients received carfilzomib at a lower dose of 20 mg/m2 for the first cycle and, if tolerated, the dose was increased to 27 mg/m2 for subsequent cycles. After the institution of IV fluids, very low-dose dexamethasone (4 mg), and the lower dose level of carfilzomib for the first cycle, the rise in creatinine levels was mitigated.

Table 2

Peripheral Neuropathy (PN). Although 72% of patients had active PN at baseline, 87% did not report AEs related to PN while receiving single-agent carfilzomib. PN AEs were mostly grade 1 or 2, rarely resulted in dose modifications or discontinuations, and new onset PN was reported infrequently (Table 2).26 These results compare favorably versus other currently approved MM therapies such as bortezomib or thalidomide.27-30

Commentary by Tiffany Richards, MS, ANP, AOCNP: PN was reported in 14% of patients in all trials of single-agent carfilzomib.17 While these results favorably compare to PN reported with other agents, PN even at a grade 1 or 2 level can be troublesome for patients. Therefore, patients should be questioned and examined for developing or worsening neuropathy at every visit. Prior to starting carfilzomib, it is essential to thoroughly evaluate the patient’s baseline PN.

Other AEs. Upper respiratory tract infections and pneumonia were reported in 28% and 13% of patients, respectively, on single-agent carfilzomib therapy.17 Gastrointestinal AEs such as nausea, diarrhea, vomiting, and constipation were common, but rarely led to treatment discontinuation or dose reductions. Abnormalities in liver function tests were also observed with carfilzomib treatment, most frequently increased serum aspartate transaminase and serum alanine transaminase. The majority of transaminase elevations were grade 1 or 2 and did not result in dose reduction or discontinuation.17

Clinical Management of AEs Associated with Single-Agent Carfilzomib
When beginning treatment, the safety profile of single-agent carfilzomib should be evaluated in conjunction with a patient’s preexisting comorbidities and toxicities from prior therapeutic regimens. Treatment-emergent AEs can be managed by following basic treatment recommendations and using appropriate prophylactic measures.

Management of Hematologic AEs. As malignant plasma cells replace bone marrow in patients with MM, cytopenia often develops, including thrombocytopenia, neutropenia, and anemia. Support with transfusion and/or hematologic growth factors is generally provided during treatment. Thrombocytopenia occurring during treatment with single-agent carfilzomib is managed with dose reduction and platelet transfusion if the platelet count falls below 25,000/mm3. In patients with grade 4 thrombocytopenia, the carfilzomib dose should be withheld until the platelet count rises above 25,000/mm3. If the platelet count recovers before the next scheduled dose, carfilzomib may be administered at the same dose level; however, if the platelet count is between 25,000/mm3 and <50,000/mm3 (grade 3 thrombocytopenia), the dose should be reduced by 1 dose level (eg, from 27 mg/m2 to 20 mg/m2 or from 20 mg/m2 to 15 mg/m2).8 If the reduced dose is tolerated, dosing may be escalated to the previous dose at the discretion of the physician. When extensive bone marrow involvement causes profound thrombocytopenia, this AE may be managed with platelet transfusions so that maximally effective carfilzomib dosing may still be maintained.31 Improved tolerability can be expected in responding patients with subsequent cycles of treatment.

Grade 3 or 4 neutropenia can be treated with granulocyte colony-stimulating factor.32 In neutropenia, the carfilzomib dose should be withheld until the absolute neutrophil count (ANC) rises to ≥1000/mm3, in general.8 If the ANC is fully recovered before the next scheduled dose, carfilzomib may be administered at the same dose level, or may be administered at a reduced dose if the ANC recovers to between 1000/mm3 and 1500/mm3 (grade 2 neutropenia). Aggressive growth factor support in patients with profound bone marrow involvement may allow maximal carfilzomib dosing to be maintained, which can result in greater efficacy and tolerability in subsequent cycles as patients respond to treatment.31

Grade 1 or 2 anemia rarely requires transfusions and may be managed with erythropoiesis-stimulating agents.12,14 For hemoglobin levels ≤10 g/dL, 40,000 units of subcutaneous epoetin alfa weekly or 300 µg of subcutaneous darbepoetin alfa every 2 weeks (or 500 µg every month) may be administered. Transfusions are usually required in patients with grade 3 or 4 anemia, and dose modifications or treatment interruptions may be required. To avoid dose interruptions, carfilzomib can be administered followed by transfusion for hemoglobin levels <8 g/dL.

Commentary by Tiffany Richards, MS, ANP, AOCNP: Myelosuppression of any grade occurs in approximately 70% of patients receiving carfilzomib with the most common grade 3 or 4 events being thrombocytopenia (23%) and anemia (22%).17 Patients require close monitoring of their blood chemistries while being treated with carfilzomib.8 When managing myelosuppression in patients with myeloma, it is important to keep in mind the etiology of the myelosuppression. If the patient has a heavily infiltrated bone marrow, then administration of blood and platelets may be required while receiving therapy. Patients and caregivers require instruction regarding signs/symptoms of bleeding and infection as well as the importance of prompt reporting, particularly if they have low blood counts prior to starting carfilzomib.

Management of Nonhematologic AEs. Dosing guidelines from the carfilzomib package insert recommend that patients receive 250 mL to 500 mL of saline prior to receiving single-agent carfilzomib in cycle 1; this can help prevent or reduce fatigue and other potential AEs such as renal toxicity and tumor lysis syndrome (TLS).8 The same amount of saline may be administered following carfilzomib dosing, and IV hydration may be continued in subsequent cycles. However, patients should be monitored for fluid overload,8 which can contribute to serious cardiac events and pulmonary complications, including cough and dyspnea. Despite adequate IV prehydration, rare cases of TLS with carfilzomib therapy of RRMM have been reported, especially in those with underlying renal dysfunction. In these patients, it may be advisable to consider TLS prophylaxis, including rasburicase or allopurinol.33

The frequency and severity of gastrointestinal AEs varies among patients with RRMM treated with single-agent carfilzomib. Nausea was generally mild and manageable in the 4 carfilz­omib phase 2 clinical trials. Premedication with an antinausea medication such as 8 mg of oral ondansetron 30 minutes prior to carfilzomib dosing may be recommended as needed.31
Antiviral and/or antibacterial prophylaxis is recommended for patients with a history of herpes virus infections or those who are at risk for certain infections, such as urinary tract infections or pneumonia.31

Commentary by Tiffany Richards, MS, ANP, AOCNP: Patients receiving carfilzomib typically require 250 mL of saline prior to carfilzomib dosing. This lower volume of saline is enough to hydrate the kidneys without placing the patient at risk for fluid overload. In patients with high tumor burden, institution of allopurinol at the start of treatment is recommended. If an increase in creatinine is noted on day 2 of carfilzomib, patients should be monitored more closely for worsening renal failure or development of tumor lysis syndrome. In addition, patients should be evaluated for diarrhea, vomiting, and other causes of renal insuffiency.

Special Clinical Concerns: Cardiac, pulmonary, renal, and hepatic AEs, while not common with carfilzomib treatment, have the potential to be serious. It is impor­tant to identify patients with a history or who are at risk for cardiac events or renal or hepatic dysfunction, in order to manage their treatment appropriately (Table 3).

Table 3

Cardiopulmonary AEs: The management of cardiac AEs begins with careful selection and evaluation of patient candidates for carfilzomib treatment. For patients who have cardiac risk factors, evaluation and clearance by a cardiologist is essential before beginning therapy.31 Once cleared, such patients should be closely monitored for fluid overload during treatment. Adjustments to antihypertensive medication may be required to manage these patients’ blood pressure while they receive carfilzomib. If a grade 3 or 4 cardiac event occurs, carfilzomib should be withheld until recovery and resumed at the physician’s discretion, based on a benefit/risk assessment.8 Most patients with shortness of breath as their primary manifestation of potential cardiac disease do not demonstrate a decrease in ejection fraction or other evidence of myocardial dysfunction. In these patients, carfilzomib may be restarted as soon as symptoms improve. In the rare patient who exhibits worsening myocardial function, echocardiographic evidence of improved cardiac function should be obtained before rechallenging with carfilzomib.31

It is important to monitor and manage dyspnea immediately, and carfilzomib dosing should be interrupted until symptoms resolve or return to baseline.8 Moreover, there are concerns that dyspnea may develop due to fluid overload rather than drug toxicity. Therefore, if a patient is not expected to tolerate aggressive hydration, serum creatinine may be monitored and, if stable, pretreatment and posttreatment hydration may be decreased or discontinued. In general, overly aggressive hydration should be avoided and patients monitored for signs and symptoms of fluid overload, including weight gain.

Renal AEs: Although a baseline evaluation of renal function is recommended prior to starting carfilzomib treatment, and creatinine clearance should be monitored throughout treatment, patients with renal dysfunction, including patients on dialysis, do not generally require dose modifications. Transient increases in serum creatinine may well be observed between consecutive carfilzomib doses and can be managed with oral and IV hydration.

Grade 3 or 4 renal AEs are uncommon with carfilzomib treatment, but when they do occur, they can be reversed by modifying the dose or discontinuing treatment. Carfilzomib should be withheld in patients with serum creatinine ≥2 × baseline until renal function has recovered to grade 1 (≤1.5 × baseline34) or baseline; dosing may be resumed at the previous dose level if it is decided that the event was unrelated to carfilzomib treatment or may be resumed at a reduced dose if the event was considered to be related to treatment.8,31

Hepatic AEs: Hepatic impairment has not typically been observed during carfilz­omib treatment; however, mild to moderate elevations in liver function enzymes may be observed from time to time. In such a case, a review of the patient’s concomitant medications is recommended and, if deemed necessary, the dose of carfilz­omib may be reduced. In cases of grade 3 or 4 elevations of transaminases or bilirubin, or other liver abnormalities, carfilzomib should be withheld until the abnormalities are resolved or return to baseline, after which carfilzomib may be resumed at a reduced rate, at the discretion of the physician.8,31

Peripheral Neuropathy: PN is rarely observed with single-agent carfilzomib use in the clinic, and there is no evidence of cumulative neurotoxicity. In the event of grade 3 or 4 PN, carfilzomib dosing should be withheld until the PN is resolved or returns to baseline; dosing may then be resumed at the dose used prior to the event or at a reduced dose at the discretion of the clinician.8,31

Infusion Reactions: Infusion reactions were observed in early clinical trials and were characterized by fever, chills, myalgia, facial swelling or flushing, vomiting, weakness, hypotension, chest tightness, or shortness of breath. Prophylactic premedication with very low-dose dexamethasone (4 mg) prior to carfilzomib in cycles 1 and 2 has been shown to decrease the incidence and severity of infusion reactions.31 If the patient tolerates the drug, dexamethasone prophylaxis may be stopped beyond cycle 1. However, if infusion reactions appear in subsequent cycles within 24 to 48 hours after receiving carfilzomib, dexamethasone should be reintroduced.8

Commentary by Tiffany Richards, MS, ANP, AOCNP: Patients require education regarding signs and symptoms of cardiopulmonary toxicities including dyspnea, edema, and chest pain. Furthermore, they should be instructed on the importance of prompt reporting to their health team or presenting to the Emergency Department. In patients with congestive heart failure, educating the patient and caregiver on daily weights and prompt reporting of weight gains between 2-5 pounds is important.

Hypertension developed in 14% of patients, with half of those patients having a prior history of hypertension.17 Therefore, patients should be instructed to monitor their blood pressure, particularly those patients with preexisting hypertension.
The majority of patients (62.7%) received herpes zoster prophylaxis while on therapy. Over the course of the 4 studies, 2.3% of patients reported herpes zoster events and 2.7% reported herpes simplex events.17

Although hepatic impairment is rare while receiving carfilzomib, patients with hepatic impairment of grade 3 or higher should have doses held until liver function studies return to baseline. If carfilzomib is resumed at a reduced dose and tolerated, the dose may be escalated to the previous dose, at the physician’s request.8 PN occurred in less than 14% of patients and was reported mostly as grade 1 or 2.17 Nevertheless, monitoring for either the development or worsening of PN should occur at each patient visit. If PN develops while on carfilzomib, dose may be reduced by 1 dose level.

Looking Ahead to the Future of Carfilzomib Therapy
Studies on carfilzomib are currently ongoing as a single agent in relapsed/refractory acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and B-cell lymphomas, and as maintenance therapy in MM, as well as a dose-finding study of higher doses of carfilzomib.30 Dose-finding studies in MM in combination with IMiDs (lenalidomide and pomalidomide), histone deacetylase inhibitors (panobinostat and vorinostat), and cytotoxic therapies (pegylated liposomal doxorubicin and cytoxan) are currently continuing.30 A phase 3 study with carfilzomib as a single agent that compares the best supportive care in RRMM is ongoing (FOCUS trial; NCT01302392).9 In addition, phase 3 trials of carfilzomib in combination with various agents in relapsed MM (ASPIRE [NCT01080391] and ENDEAVOR [NCT01568866] trials) or newly diagnosed MM (CLARION trial [NCT01818752]), are ongoing; ENDEAVOR and CLARION are recruiting patients.9,17,35,36 In Waldenström’s macroglobulinemia (WM), carfilzomib is being evaluated in combination with rituximab and dexamethasone.30

These studies seek both to expand the indications for carfilzomib across several hematologic malignancies and to further elucidate the safety profile of the drug given as a single agent and in combination with other drugs. In some cases, substituting carfilzomib for another agent in a combination regimen may reduce the toxicity of the regimen. For example, replacing bortez­omib (which is associated with considerable PN) with carfilzomib has been shown to represent a highly effective, PN-sparing approach in proteasome inhibitor–based therapy for WM.37

Commentary by Tiffany Richards, MS, ANP, AOCNP: The addition of other agents to carfilzomib is promising, with a response rate of 98% in newly diagnosed myeloma patients receiving carfilzomib, lenalidomide, and low-dose dexamethasone.38 In the RRMM setting, adding other agents to carfilzomib improves response rates and offers patients additional lines of therapy while maintaining tolerability. In Waldenström’s macroglobulinemia, response rates of 68% with a time to response of 2 months were observed with carfilzomib, rituximab, and dexamethasone.37

Conclusions
Patients with MM, particularly those with RRMM, are likely to have comorbidities and risk factors for AEs due to a number of patient- and disease-related factors, including age, prior treatments received, and the effects of the disease itself. These comorbidities include high rates of renal dysfunction and cardiac risk factors prior to treatment, and increased rates of hematologic complications and PN stemming from disease-and treatment-induced effects of prior regimens.

Given the frequency of these complications at baseline, an awareness of potential AEs with carfilzomib treatment is important for managing patients with advanced MM. Carfilzomib treatment has been well tolerated in the majority of patients, and administration of prophylactic measures and careful monitoring of patients throughout the entire course of treatment can help reduce the frequency and severity of AEs. Prevention of serious complications and subsequent dose interruptions will allow for carfilzomib to be administered at the target dose, so that patients can receive the maximal clinical benefit from its use. Ongoing studies will help further define the optimal treatment regimen for patients and will offer additional insight into the safety profile of carfilzomib.

References
1. American Cancer Society. Multiple Myeloma Detailed Guide. American Cancer Society Website www.cancer.org/cancer/multiplemyeloma/detailedguide/index. Updated February 12, 2013. Accessed February 4, 2014.
2. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2010, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2010/. Published April 2013. Accessed February 10, 2014.
3. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter International Myeloma Working Group study. Leukemia. 2012;26:149-157.
4. Lonial S, Mitsiades CS, Richardson PG. Treatment options for relapsed and refractory multiple myeloma. Clin Cancer Res. 2011;17:1264-1277.
5. Laubach J, Mitsiades M, Mahindra A, et al. Management of relapsed and relapsed/refractory multiple myeloma. J Natl Compr Canc Netw. 2011;9:1209-1216.
6. Kastritis E, Zervas K, Symeonidis A, et al. Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS): an analysis of the Greek Myeloma Study Group (GMSG). Leukemia. 2009;23:1152-1157.
7. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.
8. KYPROLIS [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; 2012.
9. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple Myeloma; Version 2.2014. NCCN Website www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed January 21, 2014.
10. Kistler K, Rajangam K, Faich G, Lanes S. Cardiac event rates in patients with newly diagnosed and relapsed multiple myeloma in US clinical practice. Blood. 2012; 120: Abstract 2916.
11. Clark A, Shetty A, Soutar R. Renal failure and multiple myeloma: Pathogenesis and treatment of renal failure and management of underlying myeloma. Blood Rev. 1999;13:79-90.
12. Faiman B, Mangan P, Spong J, Tariman J; for the International Myeloma Foundation Nurse Leadership Board. Renal complications in multiple myeloma and related disorders: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(suppl):66-76.
13. Steurer M, Wagner H, Gastl G. Prevalence and management of anaemia in haematologic cancer patients receiving cyclic nonplatinum chemotherapy: results of a prospective national chart survey. Wien Klin Wochenschr. 2004;116:367-372.
14. Maes K, Nemeth E, Roodman GD, et al. In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood. 2010;116: 3635-3644.
15. Khalafallah A, Maiwald M, Cox A, et al. Effect of immunoglobulin therapy on the rate of infections in multiple myeloma patients undergoing autologous stem cell transplantation or treated with immunomodulatory agents [published online ahead of print April 20, 2010]. Mediterr J Hematol Infect Dis. 2010;2:e2010005. doi: 10.4084/MJHID.2010.005.
16. Mateos M. Management of treatment-related adverse events in patients with multiple myeloma. Cancer Treat Rev. 2010;36:S24-S32.
17. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98:1753-1761.
18. Richardson P, Siegel D, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. Blood. 2011;118: Abstract 634.
19. Mikhael J, Belch A, Prince H, et al. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009;144:169-175.
20. van de Donk N, Lokhorst H, Dimopoulos M, et al. Treatment of relapsed and refractory multiple myeloma in the era of novel agents. Cancer Treat Rev. 2011;37: 266-283.
21. Harvey R, McCulloch L. Carfilzomib safety overview from 4 phase 2 studies. Presented at: Hematology/Oncology Pharmacy Association 9th Annual Conference; March 20-23, 2013; Los Angeles, CA. Poster 10.
22. Hazarika M, Rock E, Williams G, et al. Lenalidomide in combination with dexamethasone for the treatment of multiple myeloma after one prior therapy. Oncologist. 2008;13:1120-1127.
23. Richardson P, Sonneveld P, Schuster M, et al; for the Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498.
24. Lonial S, Niesvizky R, McCulloch L, et al. Cardiac and pulmonary safety analysis of single-agent carfilzomib treated relapsed and/or refractory multiple myeloma. Paper presented at: XIVth International Myeloma Workshop; April 2013; Kyoto, Japan. Abstract 413.
25. Badros A, Vij R, Martin T, et al. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013;27:1707-1714.
26. Martin T, Vij R, Badros A, et al. Carfilzomib is associated with a low rate of typically mild to moderate, non-dose limiting treatment-emergent peripheral neuropathy. Haematologica. 2012;97: Abstract 0857.
27. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations. Haematologica. 2010;95:311-319.
28. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.
29. Cavaletti G, Jakubowiak A. Peripheral neuropathy during bortezomib treatment of multiple myeloma: a review of recent studies. Leuk Lymphoma. 2010;51:1178-1187.
30. Nooka A, Gleason C, Casbourne D, Lonial S. Relapsed and refractory lymphoid neoplasms and multiple myeloma with a focus on carfilzomib. Biologics. 2013;7:13-32.
31. Siegel DS. From clinical trials to clinical practice: single-agent carfilzomib adverse events and their management in patients with relapsed and/or refractory multiple myeloma. Ther Adv Hematol. 2013;4:354-365.
32. Palumbo A, Bladé J, Boccadoro M, et al. How to manage neutropenia in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012;12:5-11.
33. Shely RN, Ratliff PD. Carfilzomib-associated tumor-lysis syndrome [published online ahead of print January 4, 2014]. Pharmacotherapy. 2014. doi:10.1002/phar.1397.
34. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events; Version 3.0 (CTCAE). Cancer Therapy Evaluation Program Website http://ctep.cancer.gov. Published August 9, 2006. Accessed January 8, 2014.
35. Berenson JR, Klein L, Rifkin RM, et al. A phase 1, dose-escalation study (CHAMPION-1) investigating weekly carfilzomib in combination with dexamethasone for patients with relapsed or refractory multiple myeloma. Presented at: 55th ASH Annual Meeting and Exposition; December 7-10, 2013; New Orleans, LA. Abstract 1934.
36. A multicenter, open-label, phase 1/2 study of carfilzomib, cyclophosphamide and dexamethasone induction followed by randomization to carfilzomib maintenanace versus observation in newly diagnosed multiple myeloma. NCT01980589. http://clinicaltrials.gov/ct2/results?term=NCT01980589&Search=Search. Accessed February 4, 2014.
37. Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) is highly active and offers a neuropathy sparing approach for proteasome-inhibitor based therapy in Waldenstrom’s Macroglobulinemia. Presented at: 55th ASH Annual Meeting and Exposition; December 7-10, 2013; New Orleans, LA. Abstract 757.
38. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up. J Clin Oncol. 2013;31(suppl): Abstract 8543.