This article presents an overview of the cardiac and pulmonary safety profile of single-agent carfilzomib therapy in patients with relapsed and/or refractory multiple myeloma from an analysis of four phase II clinical studies, and provides practical recommendations for the management of patients at risk for cardiac events and pulmonary complication.
Cardiac events and pulmonary complications are commonly seen in patients with multiple myeloma (MM), most of whom are over 60 years of age at the time of their diagnosis. These events and complications may be consequences of age-related comorbidities, or effects of the disease itself or current or previous treatment received. In this last category, patients who receive autologous stem cell transplant or treatment with anthracyclines, alkylating agents, immunomodulatory agents, or the proteasome inhibitor bortezomib have been found to be at increased risk for cardiovascular complications. In addition, treatment with an immunomodulatory agent or bortezomib has also been associated with pulmonary complications, which often manifest as dyspnea. An understanding of the cardiopulmonary adverse events associated with anti-MM treatment is, therefore, an important component of therapy selection. Carfilzomib is a selective proteasome inhibitor that was recently approved in the United States for the treatment of patients with relapsed and/or refractory MM who had received two or more prior therapies, including bortezomib and an immunomodulatory agent, and who demonstrated disease progression within 60 days of completion of the last therapy. This article presents an overview of the cardiac and pulmonary safety profile of single-agent carfilzomib therapy in patients with relapsed and/or refractory MM from an analysis of four phase II clinical studies, and provides practical recommendations for the management of patients at risk for cardiac events and pulmonary complications.
Multiple myeloma (MM) is most commonly diagnosed in patients between the ages of 60 and 70 years. Consequently, patients with MM often have independent comorbidities that can complicate treatment and negatively affect outcomes.[1-3] Furthermore, the pathogenesis and progression of MM can result in a number of cardiopulmonary adverse events (AEs) in addition to hematologic abnormalities (notably anemia, thrombocytopenia, and neutropenia), skeletal disease, infection, peripheral neuropathy, and compromised renal function.
Cardiac events are common in patients with MM and may occur as a result of age-related comorbidities or effects of the disease itself or as a complication of anti-MM treatment. A retrospective cohort study of more than 32,000 patients with MM in the US found a high prevalence of cardiac comorbidities, regardless of patients’ disease stage. Cardiac comorbidities were present in approximately one-third of patients at baseline, including 31% of patients with newly diagnosed MM and 37% of patients with relapsed MM. More than 70% of patients experienced a cardiac event during the study period, including congestive heart failure (CHF) in 15% of patients with newly diagnosed or relapsed MM.
Many factors can contribute to the development of cardiac disease in patients with MM, including age-related risk of cardiovascular (CV) disease and MM-associated AEs, such as chronic anemia, hemodynamically significant arteriovenous shunt, and hyperviscosity.[4-6] Amyloid light-chain amyloidosis is also present in about 10% of patients with MM and can manifest as heart failure when the heart is involved.[7,8]
Cardiac events in patients with MM have also been associated with several classes of anti-MM treatments, including chemotherapy agents, immunomodulatory drugs, and proteasome inhibitors (Table 1). Systolic left ventricular dysfunction and overt heart failure are the most frequently reported treatment-related cardiac AEs associated with cytotoxic cancer drugs, including anthracyclines (eg, doxorubicin and liposomal doxorubicin)[9,10] and alkylating agents such as cyclophosphamide.[11,12] Cyclophosphamide has additionally been associated with pericardial effusion and myopericarditis.[11,12] The proteasome inhibitor bortezomib has also been linked to CHF,[13-15] and immunomodulatory agents may be associated with higher rates of arrhythmia and myocardial infarction.[16-19] Furthermore, patients receiving stem cell transplant, particularly those receiving allogeneic stem cell transplant, are at increased risk for CV disease and cardiac arrhythmias, especially atrial fibrillation.
Pulmonary complications are also potentially serious AEs that may develop in patients with MM. Dyspnea may manifest as a symptom of multiple underlying etiologies associated with various MM therapies (eg, bortezomib, lenalidomide, and pomalidomide),[13,16,21] or it may arise as a complication of MM, including as a result of severe anemia, infection, and heart failure.
Patients with MM have an increased risk of upper and lower respiratory tract infection, particularly pneumonia, due to myeloma-related impaired immune function and myelosuppression associated with anti-MM therapies (see Table 1).[7,13,16,19,21-26] In a study of causes of mortality after MM diagnosis, 45% of deaths within 60 days resulted from infection, with pneumonia responsible for 66% of these deaths.
Given the significant impact CV and pulmonary complications have on patient morbidity and mortality, an understanding of their treatment-related incidence is important when evaluating therapeutic options. Carfilzomib is a selective, irreversible proteasome inhibitor that was recently approved in the United States for the treatment of patients with relapsed and/or refractory MM who had received two or more prior therapies, including bortezomib and an immunomodulatory agent, and who demonstrated disease progression within ≤ 60 days of completion of the last therapy. Approval was based on efficacy and/or safety results of four multicenter phase II studies (PX-171-003-A1, PX-171-003-A0, PX-171-004, and PX-171-005).[27-33] Here we review the incidence of cardiac and pulmonary AEs reported during treatment with single-agent carfilzomib and provide practical recommendations for monitoring and managing cardiopulmonary AEs during treatment.
The safety profile of single-agent carfilzomib was evaluated based on data from the four phase II studies that supported the US Food and Drug Administration approval of carfilzomib. Five hundred twenty-six patients with relapsed and/or refractory MM were enrolled across all four studies.[28-33] The median time since MM diagnosis was 4.8 years (range, 0.5–24.4 years), and patients had received a median of four prior treatment regimens. Across all four studies, patients received a median of 4 cycles (range, 1–21) of carfilzomib, and 22% of patients received 12 or more cycles of therapy or were continuing carfilzomib treatment at the time of the cross-trial safety analysis.
Patients with New York Heart Association (NYHA) class III/IV heart failure (Table 2), myocardial infarction in the preceding 6 months (3 months for the study PX-171-005), and conduction abnormalities uncontrolled by conventional medications were excluded in the phase II trials. However, it is important to note that although these patients are considered to be at greater risk for cardiac complications, the use of carfilzomib is not contraindicated in this patient population.
Overall, 22.1% of patients reported any cardiac-related AE, although 73.6% of patients had a past medical history of CV events and 70.0% had baseline cardiac risk factors (with the latter defined as a patient who reported use of at least one CV or anti-diabetic medication prior to study entry). Aggregated cardiac failure events (including CHF, pulmonary edema, and decreased ejection fraction) were reported in 38 patients (7.2%), regardless of causality. Hypertension was reported in 14.3% of patients and was mainly grade 1/2.
Arrhythmia was the most common cardiac event reported in patients receiving single-agent carfilzomib, occurring in 13.3% of patients. Most were low-grade, benign, supraventricular events, such as tachycardia or palpitations (Table 3). In general, the rate of on-study cardiac events in patients receiving single-agent carfilzomib did not increase over time (eg, 9.9% [52/526 patients] in cycle 1 vs 1.9% [3/154 patients] in cycles 9 to 11). Cardiac events of grade ≥ 3 occurred in 9.5% of patients treated with single-agent carfilzomib. Cardiac failure accounted for the majority (60%) of grade ≥ 3 cardiac events reported. Aggregated cardiac failure events, including CHF, pulmonary edema, and decreased ejection fraction, were reported in 38 patients (7.2%), regardless of causality. Ischemic heart disease was uncommon, occurring in 18 patients (3.4%).
Importantly, the majority of patients who developed CHF or ischemic heart disease during the study had baseline cardiac risk factors before receiving treatment with single-agent carfilzomib (Table 4). For example, among patients with any cardiac failure event, 87% had a history of a cardiac comorbidity, including hypertension (71%), diabetes (32%), CHF (24%), coronary artery disease (24%), and arrhythmia (21%), and among patients with any ischemic heart disease event, 89% had prior cardiac disease, including coronary artery disease (56%), hypertension (50%), diabetes (44%), myocardial infarction (28%), and arrhythmia (22%).
In response to a cardiac-related AE, 6 patients (1.1%) had a carfilzomib dose reduction and 23 patients (4.4%) discontinued treatment. Cardiac events leading to discontinuation included CHF (1.5%), cardiac arrest (1.0%), and myocardial ischemia (0.6%). Sixty-two patients (11.8%) reported a cardiac-related AE within 1 day of dosing. Eight (1.5%) cardiac-related deaths were documented, all of which were considered possibly related to single-agent carfilzomib. Of these eight deaths, cardiac events accounted for five, and an additional three patients who had disease progression noted as the primary cause of death also had a cardiac component associated with their death. Notably, the mortality rate was the same (7%) in patients who had baseline cardiac risk factors as it was for patients without baseline cardiac risk factors.
Overall, the rate of cardiac failure reported with carfilzomib treatment across the four phase II trials was similar to the rate (8%) observed in patients treated with bortezomib, and it compares favorably with the results of a retrospective cohort study of 1,723 patients with relapsed and/or refractory MM, in which CHF was reported in 15% of patients.
To reduce the risk of renal toxicity and tumor lysis syndrome in the phase II studies, patients received 250 to 500 mL of intravenous saline or other appropriate intravenous fluid before each dose of carfilzomib, plus an additional 250 to 500 mL, as needed, following carfilzomib administration. Patients were monitored for fluid overload, including severe cardiac or pulmonary events. The most commonly reported pulmonary AEs were dyspnea (42.2%) and cough (26.0%), which resulted in dose reduction in 10 patients (1.9%) and treatment discontinuation in an additional 12 patients (2.3%). The majority of dyspnea events were grade 1/2 and transient, and most resolved without dose reduction or discontinuation. Grade 3 events were recorded in 25 patients (4.8%), a rate similar to that seen with bortezomib (5%). Although no grade 4 dyspnea events were reported with carfilzomib in the four phase II trials, one patient (0.2%) with dyspnea and concurrent heart failure died. A higher percentage of dyspnea was seen in earlier cycles than in later ones (11.8% in cycle 1 vs 3.2% in cycle 6), suggesting that it was not likely to be associated with cumulative toxicity. Investigators determined that the dyspnea was possibly or probably related to single-agent carfilzomib treatment in 20.3% of patients.
Respiratory tract infections occurred in 18.8% of patients treated with single-agent carfilzomib and were reported as the primary cause of death in two patients. Pneumonia was reported in 67 patients (12.7%) and was the most common infection overall and the most common serious AE (reported in 52 patients [9.9%]). Other clinically relevant pulmonary AEs included pleural effusion (4%), pulmonary hypertension (2%), pulmonary embolism (1%), hemoptysis (0.6%), and pneumonitis (0.4%). No interstitial lung disease or pulmonary fibrosis was reported.
Because the majority of patients with MM are over 60 years of age, assessment of cardiopulmonary AEs must be considered in the context of the increased prevalence of cardiopulmonary comorbidities in this age group. However, the extent to which the cardiopulmonary events reported were attributable to patients’ baseline comorbidities, toxicity from previous treatments, effects of MM, carfilzomib treatment, or a combination of these factors cannot be determined in these single-arm trials. Prospective, randomized clinical trial analysis will be required to evaluate whether carfilzomib itself influences the development of cardiac events or whether pre-existing comorbidities (eg, cardiac arrhythmias, cardiac failure, and ischemic heart disease) contribute to the causality of these AEs, or whether both are involved. Future phase III trials are underway to further assess the effect of carfilzomib treatment in a randomized setting.
Given the risk of disease- and treatment-related cardiac events, patients with MM should be closely monitored for cardiac symptoms. It is likely that a small subset of patients will require more extensive and careful monitoring, and early identification of these patients is key. A patient with cardiac risk factors should be assessed by a cardiologist before commencing carfilzomib treatment and should be evaluated during treatment. Detailed knowledge of previous and current medications is essential for patients with a history of CV disease, and adjustment of medications may be required during carfilzomib treatment to manage blood pressure in hypertensive patients. Baseline vital signs should be recorded and monitored for changes during and after carfilzomib administration, particularly in patients with a history of hypertension, and appropriate treatment should be initiated promptly as clinically indicated. In addition, baseline and repeated echocardiograms should be considered for patients with CHF, noting the ejection fraction and any signs of pulmonary hypertension.
It is important that patients with cardiac risk factors have their body weight closely monitored to check for fluid overload. Evaluation at least once per carfilzomib treatment cycle is recommended, and we also suggest additional evaluation at week 4 for patients at increased cardiac risk. In cycle 1, patients should receive 250 mL to 500 mL of normal saline or other appropriate intravenous fluids before each dose of carfilzomib and, as needed, the same amount following carfilzomib administration, which may total approximately 3,000 mL of fluid per cycle (500 mL × 6 treatments). Hydration is recommended to reduce the risk of AEs such as renal toxicity and tumor lysis syndrome, and to prevent or reduce fatigue. However, these hydration guidelines may need to be modified on a patient-by-patient basis, particularly in those with cardiac risk factors. It is important that patients be carefully monitored for fluid overload, because overhydration may manifest as a severe cardiac or pulmonary event. Some patients may require a reduction in hydration or the addition of diuretics if they have signs or symptoms of fluid overload, including weight gain. Patients should be encouraged to monitor their dietary salt and water intake, and they should be taught to recognize signs and symptoms of fluid overload so that they may alert their healthcare team without delay.
Patients at high risk for fluid overload, such as elderly patients with a history of cardiac disease (eg, CHF), for whom 3,000 mL of fluid over 1 cycle of treatment may be a considerable burden, should have their weight monitored frequently for gains of 3 to 5 lb (1.4–2.3 kg) above baseline.[35,36] Patients who are treated with concomitant corticosteroids should also be monitored frequently because they are particularly vulnerable to fluid overload as a result of the fluid-retaining properties of steroid medications and may be at increased risk for further cardiopulmonary complications. Atrial fibrillation is common in patients with fluid overload, and dyspnea, edema, and cough may also indicate overhydration. It is important to eliminate fluid overload when determining the nature of a cardiac or pulmonary event.
For patients at risk of pulmonary infections, such as those with lymphopenia, antibacterial prophylaxis with moxifloxacin, levofloxacin, ciprofloxacin, or trimethoprim-sulfamethoxazole should be considered. Herpesvirus infection may occasionally be associated with pneumonia; prophylaxis with an antiviral agent, such as acyclovir or valacyclovir, is recommended for patients with a history of herpes zoster and can greatly reduce the risk of latent varicella-zoster virus reactivation. In the clinic, it may be advisable to administer anti-viral prophylaxis to all patients.
Overall, cardiopulmonary AEs for single-agent carfilzomib from the phase II clinical trials are similar to results reported for current MM therapies in the relapsed and/or refractory MM patient population.[13,16,33] Many of the cardiac AEs that were observed may be due, in part, to the study eligibility criteria that allowed enrollment of patients with NYHA class II cardiac disease.
In conclusion, while the cardiac and pulmonary complications described in these trials are of concern, it is important to appreciate that carfilzomib dose reductions and discontinuations due to cardiac or pulmonary AEs were uncommon. Patients should be evaluated for baseline CV risk before treatment and appropriately monitored for fluid overload and cardiac or pulmonary complications. If these AEs are managed proactively and aggressively when they first arise, patients can derive maximum benefit from their treatment with carfilzomib.
Financial Disclosure:Dr. Wang receives support from Onyx for laboratory and clinical trials research. Dr. Cheng has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Acknowledgment:The authors thank Tom Martin, MD, of the University of California at San Francisco Medical Center for critical review of this manuscript. Medical writing and editorial assistance was provided by BlueMomentum, a division of KnowledgePoint360 Group, San Bruno, California, and funded by Onyx Pharmaceuticals, Inc.
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma, version 2.2013. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site.
2. Sirohi B, Powles R. Multiple myeloma. Lancet. 2004;363:875-87.
3. Raab MS, Podar K, Breitkreutz I, et al. Multiple myeloma. Lancet. 2009;374:324-39.
4. Kistler KD, Rajangam K, Faich G, et al. Cardiac event rates in patients with newly diagnosed and relapsed multiple myeloma in US clinical practice. Blood. 2012;119:abstr 2916.
5. McBride W, Jackman JD, Jr, Gammon RS, Willerson JT. High-output cardiac failure in patients with multiple myeloma. N Engl J Med. 1988;319:1651-3.
6. Inanir S, Haznedar R, Atavci S, Unlu M. Arteriovenous shunting in patients with multiple myeloma and high-output failure. J Nucl Med. 1998;39:1-3.
7. Pingali SR, Haddad RY, Saad A. Current concepts of clinical management of multiple myeloma. Dis Mon. 2012;58:195-20.
8. Meyer T, Shih J, Aurigemma G. Heart failure with preserved ejection fraction (diastolic dysfunction). Ann Intern Med. 2013;158:ITC5-1-15.
9. Smith LA, Cornelius VR, Plummer CJ, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010; 10:337.
10. Armenian SH, Sun CL, Vase T, et al. Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of subsequent cardiovascular disease. Blood. 2012;120:4505-12.
11. Colombo A, Cipolla C, Beggiato M, et al. Cardiac toxicity of anticancer agents. Curr Cardiol Rep. 2013; 15:362.
12. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2012;23(suppl 7): vii155-66.
13. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005; 352:2487-98.
14. Velcade (bortezomib) prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc.; 2012.
15. Honton B, Despas F, Dumonteil N, et al. Bortezomib and heart failure: case-report and review of the French Pharmacovigilance database. Fundam Clin Pharmacol. 2013 May 24. [Epub ahead of print]
16. 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;13:1120-7.
17. Revlimid (lenalidomide) capsules prescribing information. Summit, NJ: Celgene Corporation; 2013.
18. Thalomid (thalidomide) capsules prescribing information. Summit, NJ: Celgene Corporation; 2013.
19. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood. 2008;111:3968-77.
20. Sureddi RK, Amani F, Hebbar P, et al. Atrial fibrillation following autologous stem cell transplantation in patients with multiple myeloma: incidence and risk factors. Ther Adv Cardiovasc Dis. 2012;6:229-36.
21. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011;118:2970-5.
22. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892-901.
23. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-42.
24. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007; 357: 2123-32.
25. Pomalyst (pomalidomide) capsules prescribing information. Summit, NJ: Celgene Corporation; 2013.
26. Augustson BM, Begum G, Dunn JA, et al. Early mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United Kingdom Medical Research Council trials between 1980 and 2002-Medical Research Council Adult Leukaemia Working Party. J Clin Oncol. 2005;23:9219-26.
27. Kyprolis (carfilzomib) prescribing information. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.
28. 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;120:2817-25.
29. Jagannath S, Vij R, Stewart AK, et al. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012;12:310-8.
30. Vij R, Wang M, Kaufman JL, et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012;119:5661-70.
31. Vij R, Siegel DS, Jagannath S, et al. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012;158:739-48.
32. Badros AZ, Vij R, Martin T, et al. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013;27:1704-14.
33. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase 2 clinical studies. Haematologica. 2013 Aug 9. [Epub ahead of print]
34. American Heart Association. New York Heart Association (NYHA) Functional Classification. Classes of heart failure. Available from: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeart Failure/Classes-of-Heart-Failure_UCM_306328_Article.jsp.
35. McBride L, Samuel CO. The side effect profile of carfilzomib: from clinical trials to clinical practice. J Adv Pract Oncol. In press.
36. Tuy T, Peacock WF 4th. Fluid overload assessment and management in heart failure patients. Semin Nephrol. 2012;32:112-20.
37. Voroneanu L, Covic A. Arrhythmias in hemodialysis patients. J Nephrol. 2009;22:716-25.