Amgen issued the following announcement on August 20.
Amgen (NASDAQ:AMGN) today announced the U.S. Food and Drug Administration (FDA) has approved the expansion of the KYPROLIS® (carfilzomib) U.S. prescribing information to include its use in combination with DARZALEX® (daratumumab) plus dexamethasone (DKd) in two dosing regimens — once weekly and twice weekly — for the treatment of patients with relapsed or refractory multiple myeloma (R/R MM) who have received one to three previous lines of therapy.
"This expanded approval for KYPROLIS demonstrates a leap forward in the treatment paradigm for this complex disease by combining two potent agents in their respective drug classes indicated for patients with relapsed or refractory multiple myeloma," said David M. Reese, M.D., executive vice president of Research and Development at Amgen.
Multiple myeloma is a blood cancer characterized by patterns of remission and relapse. Patient outcomes worsen with each relapse.1 With the increasing use of frontline immunomodulatory drug based (IMiD) therapies through progression, the number of patients treated with these agents who will progress is likely to increase with time. This creates an emerging need for efficacious lMiD-free regimens upon relapse.2
"Now, we can provide healthcare professionals and patients with an efficacious regimen with two dosing options at a critical time in a patient's treatment journey: first relapse," Reese continued.
"The DKd regimen provides an important potent triplet option in the setting of relapse following IMiD combination frontline therapy," said Brian G.M. Durie, M.D., chairman, International Myeloma Foundation.
The Phase 3 CANDOR trial was the first Phase 3 randomized trial to compare DKd versus KYPROLIS and dexamethasone (Kd) alone in R/R MM patients. The study met its primary endpoint and resulted in a 37% reduction in the risk of disease progression or death in patients receiving DKd (HR=0.63; 95% CI: 0.464, 0.854; p-value [1-sided]=0.0014) compared to Kd alone.
"Despite ongoing advances in the treatment of multiple myeloma, the disease remains incurable and is especially challenging for patients who relapse or become refractory to established therapies," said Saad Z. Usmani, M.D., director of clinical research in hematologic malignancies; director of plasma cell disorders; clinical professor of medicine, Atrium Health's Levine Cancer Institute. "As a clinician, having the DKd regimen as an option means we can now combine two efficacious, targeted agents in a new, immunomodulatory drug-free triplet regimen that has demonstrated deep and durable responses for patients upon relapse."
In CANDOR, the safety of DKd was generally consistent with the known safety profiles of the individual agents. The most frequently reported (≥ 20% of subjects in either treatment arm [DKd, Kd]) treatment-emergent adverse events (AEs) included infusion-related reactions, anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, neutropenia, lymphopenia, cough, dyspnea, and insomnia, headache and back pain. The incidence of treatment-emergent Grade 3 or higher, serious and fatal AEs was higher in the DKd arm compared to the Kd arm. The most common reason for fatal treatment-emergent AEs in both arms was infection. The rate of treatment discontinuation due to AEs was similar in both arms.
The expansion of KYPROLIS's prescribing information to include once-weekly dosing of KYPROLIS within the DKd regimen was supported by the open-label, multi-cohort Phase 1b EQUULEUS trial, in which the safety and efficacy of DKd was assessed among R/R MM patients using a once-weekly dosing regimen for KYPROLIS.
Amgen has submitted marketing applications globally.
DARZALEX® is a registered trademark of Janssen Pharmaceutica NV.
About CANDOR
CANDOR, a randomized, open-label Phase 3 study of KYPROLIS, DARZALEX and dexamethasone (DKd) compared to KYPROLIS and dexamethasone (Kd), has evaluated 466 relapsed or refractory multiple myeloma patients who have received one to three prior therapies. Patients were treated until disease progression. The primary endpoint was progression-free survival (PFS), and the key secondary endpoints were overall response rate, minimal residual disease and overall survival. PFS was defined as time from randomization until disease progression or death from any cause.
In the first arm, patients received KYPROLIS twice weekly at 56 mg/m2 and dexamethasone in combination with DARZALEX. In the second arm (control), patients received KYPROLIS twice weekly at 56 mg/m2 and dexamethasone.
CANDOR was initiated as part of a collaboration with Janssen, and under the terms of the agreement, Janssen co-funded the study. For more information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT03158688.
About EQUULEUS
EQUULEUS was an open label, Phase 1b, multi-cohort trial which evaluated the combination of KYPROLIS with intravenous DARZALEX and dexamethasone in 85 patients with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy.
KYPROLIS was evaluated at a starting dose of 20 mg/m2, which was increased to 70 mg/m2 on Cycle 1, Day 8 and onward.
The most frequently reported all-grade, treatment-emergent AEs (occurring in 20% or more of patients) were thrombocytopenia, respiratory tract infection, anemia, nausea, fatigue, vomiting, diarrhea, pyrexia, neutropenia, lymphopenia, infusion related reactions, dyspnea, cough, insomnia, hypertension, headache and back pain.
At a median follow-up of 16.6 months, the overall response rate was 81% in all treated patients: 21% achieved a stringent complete response, 14% a complete response, 33% a very good partial response and 13% a partial response.
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.3 It is a rare and life-threatening disease that accounts for approximately one percent of all cancers.4,5 Worldwide, approximately 160,000 people are diagnosed with multiple myeloma each year, and 106,000 patient deaths are reported on an annual basis.4
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.6,7
Since its first approval in 2012, approximately 150,000 patients worldwide have received KYPROLIS.8 KYPROLIS is approved in the U.S. for the following:
- for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with
- Lenalidomide and dexamethasone; or
- Dexamethasone; or
- Daratumumab and dexamethasone.
- as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
U.S. KYPROLIS® (carfilzomib) Important Safety Information
INDICATIONS
- KYPROLIS® (carfilzomib) is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
- KYPROLIS® is indicated as a single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
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 administration.
- Monitor patients for signs or symptoms of cardiac failure or 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 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.
- For 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 prior to starting treatment with KYPROLIS and remain under close follow-up with fluid management.
- Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency adverse events (including renal failure) have occurred. 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.
- Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred. Patients with 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, and withhold until resolved.
- Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred. Some events have been fatal. In the event of drug–induced pulmonary toxicity, discontinue KYPROLIS.
- Pulmonary arterial hypertension (PAH) was reported. 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 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 based on a benefit/risk assessment.
- Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some fatal. Control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart based on a benefit/risk assessment.
- Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed. 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 hormonal contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment.
- Infusion reactions, including life–threatening reactions, have occurred. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal 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. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms and seek immediate medical attention if they occur.
- Fatal or serious cases of hemorrhage have been reported. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
- KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Monitor platelet counts frequently during treatment. Reduce or withhold dose as appropriate.
- Cases of hepatic failure, including fatal cases, have occurred. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
- Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome, have occurred. Monitor for signs and symptoms of TTP/HUS. Discontinue if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS is not known.
- Cases of PRES have occurred in patients receiving KYPROLIS. If PRES is suspected, discontinue and evaluate with appropriate imaging. The safety of reinitiating KYPROLIS is not known.
- In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm. KMP is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.
- KYPROLIS can cause fetal harm when administered to a pregnant woman.
- Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS and for 6 months following the final dose. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS and for 3 months following the final dose. 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.
- The most common adverse reactions in the combination therapy trials: anemia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, cough, upper respiratory tract infection, hypertension.
- The most common adverse reactions in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.
About Amgen Oncology
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About Amgen
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.
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