ASH Clinical News April 2016 | Page 64

Care Path of Least Resistance images should be obtained and when, what laboratory values are needed, the preferred initial treatment plan, which drug regimen to use and how often, and what surveillance strategy should be used. Critical to this process is identifying the evidence that supports these decisions. Care paths can be developed at an institutional level, or by a committee of experts at a medical society or national level, ideally using standardized methodology in identifying preferred treatment strategies in the absence of any conflict of interest. “There are many ways to treat cancers – more than ever – and by coming up with a common approach, there is a simple reduction in variability that reduces people ordering whatever they want, whenever they want, without the data to back up those decisions,” Dr. Bolwell said. “Things get standardized and fewer resources are consumed.” At Cleveland Clinic, Dr. Bolwell said that multidisciplinary teams meet several times a year to keep these care paths current, incorporating the newest technology or drugs. They also embed quality metrics into the paths to track their use and efficacy. “For example, for some cancers treated by surgery, the number of lymph nodes sampled is a quality metric,” he explained. “Or for B-cell lymphoma, a quality metric might measure whether or not the patient got a pretreatment PET scan.” By tracking these metrics, the institution can track adherence to a pathway and identify areas for improvement. Increased Value According to Dr. Longworth, data that back up the idea that clinical care paths provide value and save resources are only beginning to emerge. Most of the evidence at this point is anecdotal. At the 2014 ASH Annual Meeting, Dr. Bolwell and colleague s presented early data from a study conducted at Cleveland Clinic about the care path for upfront treatment of patients with myeloma, finding that most patients achieved uniform disease control using fewer drugs than the standard approach.1 In the pathway, patients with multiple myeloma were started on a two-drug regimen (lenalidomide and dexamethasone) as opposed to a three-drug regimen (bortezomib, lenalidomide, and dexamethasone), both of which may be considered standards of care. Care-path developers selected the two-drug regimen to avoid the higher risk for side effects (including peripheral neuropathy), and higher costs associated with the three-drug regimen, without a clear-cut improvement in overall survival. If patients did not have at least a minimal response (<50% decrease in M protein) after the first treatment cycle, or at least partial response (>50% decrease in M protein) after the second cycle, treatment could be adapted with sequential addition of agents. After 15 months of implementation, the 24 patients who were treated following the care path achieved minimal response or better, with 60 percent of patients requiring treatment with only two drugs. “Overall survival will be the ultimate assessment of the utility of this approach, but response assessments to date support ongoing utilization of the care path,” the authors wrote. In addition, compared with standard use of the threedrug regimen, an adapted approach reduced the risk of peripheral neuropathy and lowered costs, with a savings in drug costs alone of more than $4,000 per treatment cycle. More recently, at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, Cleveland Clinic researchers presented data from an evaluation of a clinical care path’s effect on treatment decisions and health-care costs for non-small cell lung cancer.2 In INDICATION AND IMPORTANT SAFETY INFORMATION INDICATION KYPROLIS® (carfilzomib) is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. IMPORTANT SAFETY INFORMATION Cardiac Toxicities: New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration. • Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment. • While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure. • Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up. Acute Renal Failure: Cases of acute renal failure and renal insufficiency adverse events (including renal failure) have occurred in patients receiving KYPROLIS. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate. Tumor Lysis Syndrome: Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving KYPROLIS. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold KYPROLIS until TLS is resolved. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving KYPROLIS. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS. Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in patients treated with KYPROLIS. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment. Dyspnea: Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart KYPROLIS based on a benefit/risk assessment. Hypertension: Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with KYPROLIS. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart KYPROLIS based on a benefit/risk assessment. Venous Thrombosis: Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have bee n observed with KYPROLIS. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks. • Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone. Infusion Reactions: Infusion reactions, including life-threatening reactions, have occurred in patients receiving KYPROLIS. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur. Thrombocytopenia: KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving KYPROLIS. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or withhold dose as appropriate. Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported during treatment with KYPROLIS. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate. Thrombotic Microangiopathy: Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in patients receiving KYPROLIS. Monitor for signs and symptoms of TTP/HUS. Discontinue KYPROLIS if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS therapy in patients previously experiencing TTP/HUS is not known. Posterior Reversible Encephalopathy Syndrome (PRES): Cases of PRES have occurred in patients receiving KYPROLIS. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known. Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. • Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS • The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch or call 1-800-FDA-1088. Please see Brief Summary of full Prescribing Information on adjacent pages. ©2016 Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary, Thousand Oaks, CA USA-171-120752 February 2016 Printed in USA 62 ASH Clinical News