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European Commission Approves Kyprolis® (carfilzomib) For Combination Use In The Treatment Of Patients With Relapsed Multiple Myeloma
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"The approval of Kyprolis in combination provides physicians and patients across
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.2 It is a rare and very aggressive orphan disease that accounts for approximately one percent of all cancers.3-5 In
"In clinical studies, approximately one out of three patients achieved a complete response or better on the Kyprolis in combination with lenalidomide and dexamethasone arm, which is three times more frequent than in the lenalidomide and dexamethasone arm," said Prof.
The EC approved Kyprolis based on data from the pivotal Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial. The study showed that patients treated with Kyprolis in combination with lenalidomide and dexamethasone (regimen referred to as KRd) had increased median time to progressive disease (PD) or death by 8.7 months compared to patients treated with lenalidomide and dexamethasone (regimen referred to as Rd). The median progression-free survival (PFS) was 26.3 months in the KRd arm compared to 17.6 months in the Rd arm (HR: 0.69; 95 percent CI: 0.57 to 0.83; p=0.0001). The most common adverse events (AEs) in the Kyprolis arm included pneumonia (1 percent), myocardial infarction (0.8 percent) and upper respiratory tract infection (0.8 percent). Discontinuation of treatment due to AEs occurred in 15 percent of patients in the KRd arm versus 18 percent of patients in the Rd arm.
Kyprolis received an accelerated assessment from the
Approval from the EC grants a centralized marketing authorization with unified labeling in the 28 countries that are members of the EU.
The international, randomized Phase 3 ASPIRE trial evaluated Kyprolis in combination with lenalidomide and dexamethasone, versus lenalidomide and dexamethasone, in patients with relapsed multiple myeloma following treatment with one to three prior regimens. The primary endpoint of the trial was PFS, defined as the time from randomization to disease progression or death due to any cause, whichever is earlier. Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), disease control rate, health-related quality of life (HR-QoL) and safety. Patients were randomized to receive Kyprolis (20 mg/m2 on days 1 and 2 of cycle one, escalating, if tolerated, to 27 mg/m2 subsequently), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and dexamethasone (40 mg per week in 4 week cycles), versus lenalidomide and dexamethasone. In the Kyprolis arm, patients were given a 10 minute infusion on days 1, 2, 8, 9, 15 and 16. Kyprolis was omitted on days 8 and 9 during cycles 13-18 and not administered beyond 18 cycles. The study randomized 792 patients at sites in
While the data for median OS were not yet mature at the time of primary analysis, the analysis showed a trend in favor of KRd compared with Rd (HR=0.79; 95 percent CI: 0.63-0.99; p=0.02 [1-sided]). Patients continue to be monitored for OS. The ORR was 87.1 percent with KRd and 66.7 percent with Rd. Median DOR was 28.6 months for patients receiving KRd (95 percent CI, 24.9 to 31.3 months) and 21.2 months for patients receiving Rd (95 percent CI, 16.7 to 25.8 months). In the KRd and Rd groups, 32 percent versus 9 percent of patients achieved a complete response or higher (stringent complete response [sCR] or complete response [CR]), a measurement indicating depth of response.
The rate of death due to AEs within 30 days of the last dose was balanced between the KRd arm and the Rd arm. The most common causes of death not due to PD occurring in patients in the KRd arm compared to the Rd arm included cardiac disorders (3 percent versus 2 percent), infection (2 percent versus 3 percent), renal (0 percent versus less than 1 percent) and other AEs (2 percent versus 3 percent). Serious AEs (SAEs) were reported in 60 percent of the patients in the KRd arm and 54 percent of the patients in the Rd arm. The most common SAEs reported in the KRd arm compared to the Rd arm were pneumonia (14 percent versus 11 percent), respiratory tract infection (4 percent versus 2 percent), pyrexia (4 percent versus 2 percent) and pulmonary embolism (3 percent versus 2 percent). Discontinuation of treatment due to AEs occurred in 15 percent of patients in the KRd arm versus 18 percent of patients in the Rd arm. AEs leading to discontinuation of Kyprolis occurred in 12 percent of patients and the most common events included pneumonia (1 percent), myocardial infarction (1 percent) and upper respiratory tract infection (1 percent).
The ASPIRE data were presented at the 56th Annual Meeting of the
About Kyprolis® (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.6 Kyprolis has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.7 In some cells, Kyprolis can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.7 The irreversibility of Kyprolis' binding has also been shown to offer a more sustained inhibition of the targeted enzymes.8
Kyprolis is currently approved in the U.S. in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior lines of therapy.
Kyprolis is also indicated under
Kyprolis is also approved in
Kyprolis is a product of
Important EU Product Safety Information
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy. The most serious side effects that may occur during Kyprolis treatment include: cardiac toxicity, pulmonary toxicities, pulmonary hypertension, dyspnoea, hypertension including hypertensive crises, acute renal failure, tumour lysis syndrome, infusion reactions, thrombocytopenia, hepatic toxicity, posterior reversible encephalopathy syndrome (PRES) and thrombotic thrombocytopenic purpura/haemolytic uremic syndrome (TTP/HUS). The most common side effects are anaemia, fatigue, diarrhoea, thrombocytopenia, nausea, pyrexia, dyspnoea, respiratory tract infection, cough and peripheral oedema.
Please refer to the Summary of Product Characteristics for full European prescribing information.
Important U.S. Product Safety Information
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. Death due to cardiac arrest has occurred within a day of Kyprolis administration.
Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis based on a benefit/risk assessment.
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, and conduction abnormalities may be at greater risk for cardiac complications.
Acute Renal Failure
Cases of acute renal failure and renal insufficiency adverse events (renal impairment, acute renal failure, 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. This risk was greater in patients with a baseline reduced estimated creatinine clearance. 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.
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 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 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, 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 thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. Thromboprophylaxis is recommended and should be based on an assessment of the patient's underlying risks, treatment regimen, and clinical status.
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.
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. Reduce or withhold dose as appropriate.
Thrombotic Thrombocytopenic Purpura /Hemolytic Uremic Syndrome (TTP/HUS)
Cases of 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, such as seizure, headache, lethargy, confusion, blindness, and altered consciousness, along with hypertension.. Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.
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 and the potential hazard to the fetus if Kyprolis is used during pregnancy.
The most common adverse events of all grades occurring in at least 20 percent of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, decreased platelets, dyspnea, diarrhea, decreased lymphocyte, headache, decreased hemoglobin, cough, edema peripheral.
The most common adverse events of all grades occurring in at least 20 percent of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia.
Full prescribing information for the U.S. is available at www.kyprolis.com.
Forward Looking Statements
This news release contains forward-looking statements that are based on the current expectations and beliefs of
In addition, sales of our products (including products of our wholly-owned subsidiaries) are affected by the reimbursement policies imposed by third-party payers, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment as well as U.S. legislation affecting pharmaceutical pricing and reimbursement. Government and others' regulations and reimbursement policies may affect the development, usage and pricing of our products. In addition, we compete with other companies with respect to some of our marketed products as well as for the discovery and development of new products. We believe that some of our newer products, product candidates or new indications for existing products, may face competition when and as they are approved and marketed. Our products may compete against products that have lower prices, established reimbursement, superior performance, are easier to administer, or that are otherwise competitive with our products. In addition, while we and our partners routinely obtain patents for our and their products and technology, the protection of our products offered by patents and patent applications may be challenged, invalidated or circumvented by our or our partners' competitors and there can be no guarantee of our or our partners' ability to obtain or maintain patent protection for our products or product candidates. We cannot guarantee that we will be able to produce commercially successful products or maintain the commercial success of our existing products. Our stock price may be affected by actual or perceived market opportunity, competitive position, and success or failure of our products or product candidates. Further, the discovery of significant problems with a product similar to one of our products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on our business and results of operations. Our efforts to integrate the operations of companies we have acquired may not be successful. We may experience difficulties, delays or unexpected costs and not achieve anticipated benefits and savings from our ongoing restructuring plan. Our business performance could affect or limit the ability of our Board of Directors to declare a dividend or our ability to pay a dividend or repurchase common stock.
- Stewart KA, Rajkumar VS, Dimopoulos MA, et al. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med. 2015; 372:142-152.
- Jakubowiak A. Management Strategies for Relapsed/Refractory Multiple Myeloma: Current Clinical Perspectives. Seminars in Hematology. 2012; 49(3)(1),S16-S32.
- GLOBCAN 2012, Global Prevalence and Incidence, available at http://globocan.iarc.fr/old/summary_table_pop_prev.asp?selection=224900&title=World&sex=0&window=1&sort=0&submit=%C2%A0Execute%C2%A0, accessed on
March 9, 2015. American Cancer Society. Multiple myeloma. http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf. Accessed on: October 30, 2015.
- Palumbo A and Anderson K, Multiple myeloma, N Engl J Med, 2011;364:1046–60
- Moreau P, Richardson PG, Cavo M, et al. Proteasome Inhibitors in Multiple Myeloma: 10 Years Later. Blood. 2012; 120(5):947-959.
- Kyprolis® [package insert].
Thousand Oaks, CA: Amgen; 2015.
- Kortuem KM and Stewart AK. Carfilzomib. Blood. 2012; 121(6):893-897.
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