THOUSAND OAKS, Calif.,
Aug. 20, 2020 /PRNewswire/ -- 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.
KYPROLIS is also approved in Algeria, Argentina, Australia, Bahrain, Belarus, Brazil, Canada, Chile, Colombia, Ecuador, Egypt, European Union, Hong Kong, India, Israel, Japan, Jordan, Kazakhstan, Kuwait, Lebanon, Macao, Malaysia, Mexico, Morocco, New
Zealand, Oman, Peru, Philippines, Qatar, Russia, Saudi
Arabia, Serbia, Singapore,
S. Africa, S. Korea, Switzerland,
Taiwan, Thailand, Turkey and United
Arab Emirates.
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.
IMPORTANT SAFETY INFORMATION FOR KYPROLIS
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.
Acute Renal Failure
- 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.
Tumor Lysis Syndrome
- 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.
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. Some
events have been fatal. In the event of drug–induced pulmonary
toxicity, discontinue KYPROLIS.
Pulmonary Hypertension
- 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
- 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
- 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 Thrombosis
- 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
- 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.
Hemorrhage
- 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.
Thrombocytopenia
- 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.
Hepatic Toxicity and Hepatic Failure
- 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.
Thrombotic Microangiopathy
- 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.
Posterior Reversible Encephalopathy Syndrome
(PRES)
- 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.
Increased Fatal and Serious Toxicities in Combination with
Melphalan and Prednisone in Newly Diagnosed
Transplant-ineligible Patients
- 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.
Embryo-fetal Toxicity
- 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.
Adverse Reactions
- 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.
Please see accompanying full Prescribing Information
at www.kyprolis.com.
About Amgen Oncology
Amgen Oncology is searching for and finding answers to incredibly
complex questions that will advance care and improve lives for
cancer patients and their families. Our research drives us to
understand the disease in the context of the patient's life – not
just their cancer journey – so they can take control of their
lives.
For the last four decades, we have been dedicated to discovering
the firsts that matter in oncology and to finding ways to reduce
the burden of cancer. Building on our
heritage, Amgen continues to advance the largest pipeline
in the Company's history, moving with great speed to advance those
innovations for the patients who need them.
At Amgen, we are driven by our commitment to transform the
lives of cancer patients and keep them at the center of everything
we do.
For more information, follow us
on www.twitter.com/amgenoncology.
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.
Amgen focuses on areas of high unmet medical need and
leverages its expertise to strive for solutions that improve health
outcomes and dramatically improve people's lives. A biotechnology
pioneer since 1980, Amgen has grown to be one of the
world's leading independent biotechnology companies, has reached
millions of patients around the world and is developing a pipeline
of medicines with breakaway potential.
For more information, visit www.amgen.com and follow
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CONTACT: Amgen, Thousand Oaks
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References:
- Jakubowiak A. Management strategies for relapsed/refractory
multiple myeloma: current clinical perspectives. Semin
Hematol. 2012 Jul; 49 Suppl 1: S16-S32.
- Moreau P., et al. Treatment of patients with multiple myeloma
progressing on frontline-therapy with lenalidomide. Blood Cancer
J. (2019)9:38.
https://doi.org/10.1038/s41408-019-0200-1.
- Kumar S., et al. NCCN Guidelines Insights: Multiple Myeloma.
The Journal of the National Comprehensive Cancer Network.
Jan 2018; Volume 16: Issue 1.
https://doi.org/10.6004/jnccn.2018.0002.
- Jakubowiak A. Management strategies for relapsed/refractory
multiple myeloma: current clinical perspectives. Semin
Hematol. 2012 Jul; 49 Suppl 1: S16-S32.
- GLOBOCAN 2018. Multiple Myeloma. Available
at: http://gco.iarc.fr/today/data/factsheets/cancers/35-Multiple-myeloma-fact-sheet.pdf.
Accessed November 15, 2019.
- Moreau P, Richardson PG, Cavo M, et al. Proteasome inhibitors
in multiple myeloma: 10 years later. Blood.
2012 Aug 2;120(5):947-59.
- Kortuem KM and Stewart AK. Carfilzomib. Blood.
2013 Feb 7;121(6):893-7.
- Amgen Data on File.
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