ASH News Daily 2017 - Issue 3 - B-14

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KYPROLIS® (carfilzomib) for injection, for intravenous use
Brief Summary of Prescribing Information.
Please see the KYPROLIS package insert for full prescribing information.
1. INDICATIONS AND USAGE
* Kyprolis 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.
* Kyprolis is indicated as a single agent for the treatment of patients with relapsed or refractory multiple
myeloma who have received one or more lines of therapy.
5. WARNINGS AND PRECAUTIONS
5.1 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. In clinical studies with Kyprolis, these events occurred
throughout the course of Kyprolis therapy. Death due to cardiac arrest has occurred within one day of
Kyprolis administration. In a randomized, open-label, multicenter trial evaluating Kyprolis in combination
with lenalidomide and dexamethasone (KRd) versus lenalidomide/dexamethasone (Rd), the incidence
of cardiac failure events was 6% in the KRd arm versus 4% in the Rd arm. In a randomized, open-label,
multicenter trial of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd), the
incidence of cardiac failure events was 8% in the Kd arm versus 3% in the Vd arm.
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,
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, all patients should also be monitored
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.
In patients ≥ 75 years of age, the risk of cardiac failure is increased compared to patients < 75 years of
age. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction,
conduction abnormalities, angina, or arrhythmias uncontrolled by medications were not eligible for
the clinical trials. These patients 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.
5.2 Acute Renal Failure
Cases of acute renal failure have occurred in patients receiving Kyprolis. Renal insufficiency adverse
events (including renal failure) have occurred in approximately 10% of patients treated with 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 (calculated using Cockcroft and Gault equation). Monitor renal function with
regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold
dose as appropriate.
5.3 Tumor Lysis Syndrome
Cases of tumor lysis syndrome (TLS), including fatal outcomes, have been reported in patients who received
Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk
for TLS. Ensure that patients are well hydrated before administration of Kyprolis 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, including interruption of Kyprolis until TLS is resolved.
5.4 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 less than 1%
of patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary
toxicity, discontinue Kyprolis.
5.5 Pulmonary Hypertension
Pulmonary arterial hypertension was reported in approximately 1% of patients treated with Kyprolis and
was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests
as indicated. Withhold Kyprolis for pulmonary hypertension until resolved or returned to baseline, and
consider whether to restart Kyprolis based on a benefit/risk assessment.
5.6 Dyspnea
Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4% of
patients. 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.
5.7 Hypertension
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis.
In a randomized, open-label, multicenter trial evaluating Kyprolis in combination with KRd versus Rd, the
incidence of hypertension events was 16% in the KRd arm versus 8% in the Rd arm. In a randomized,
open-label, multicenter trial of Kd versus Vd, the incidence of hypertension events was 26% in the Kd arm
versus 10% in the Vd arm. 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.
5.8 Venous Thrombosis
Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been
observed with Kyprolis. In a randomized, open-label, multicenter trial evaluating KRd versus Rd (with
thromboprophylaxis used in both arms), the incidence of venous thromboembolic events in the first 12
cycles was 13% in the KRd arm versus 6% in the Rd arm. In a randomized, open-label, multicenter trial of
Kd versus Vd, the incidence of venous thromboembolic events in months 1-6 was 9% in the Kd arm versus
2% in the Vd arm. With Kyprolis monotherapy, the incidence of venous thromboembolic events was 2%.
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.
5.9 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. Administer dexamethasone prior
to Kyprolis to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of
symptoms and to contact a physician immediately if symptoms of an infusion reaction occur.
5.10 Hemorrhage
Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis. Hemorrhagic
events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. The bleeding
can be spontaneous, and intracranial hemorrhage has occurred without trauma. Hemorrhage has been
reported in patients having either low or normal platelet counts. Hemorrhage has also been reported in
patients who were not on antiplatelet therapy or anticoagulation. Promptly evaluate signs and symptoms
of blood loss. Reduce or withhold dose as appropriate.

5.11 Thrombocytopenia
Kyprolis causes thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 of each 28-day
cycle, with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was
reported in approximately 40% of patients in clinical trials with Kyprolis. Monitor platelet counts frequently
during treatment with Kyprolis. Reduce or withhold dose as appropriate. Hemorrhage may occur.
5.12 Hepatic Toxicity and Hepatic Failure
Cases of hepatic failure, including fatal cases, have been reported (< 1%) during treatment with Kyprolis.
Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly, regardless of
baseline values. Reduce or withhold dose as appropriate.
5.13 Thrombotic Microangiopathy
Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic
syndrome (TTP/HUS), have been reported in patients who received Kyprolis. Some of these events have
been fatal. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Kyprolis and
evaluate. 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.
5.14 Posterior Reversible Encephalopathy Syndrome
Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving
Kyprolis. PRES, formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a
neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered
consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis
is confirmed by neuro-radiological imaging (MRI). Discontinue Kyprolis if PRES is suspected and evaluate.
The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.
5.15 Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in
Newly Diagnosed Transplant-Ineligible Patients
In a clinical trial of 955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized
to Kyprolis (20/36 mg/m2 by 30-minute infusion twice weekly for four of each six-week cycle), melphalan,
and prednisone (KMP) or bortezomib, melphalan, and prednisone (VMP), a higher incidence of fatal
adverse reactions (7% versus 4%) and serious adverse reactions (50% versus 42%) were observed in
the KMP arm compared to patients in the VMP arm, respectively. Patients in the KMP arm were observed
to have a higher incidence of any grade adverse reactions involving cardiac failure (11% versus 4%),
hypertension (25% versus 8%), acute renal failure (14% versus 6%), and dyspnea (18% versus 9%).
This study did not meet its primary outcome measure of superiority in progression-free survival for the
KMP arm. Kyprolis in combination with melphalan and prednisone is not indicated for transplant-ineligible
patients with newly diagnosed multiple myeloma.
5.16 Embryo-Fetal Toxicity
Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action
and findings in animals. There are no adequate and well-controlled studies in pregnant women using Kyprolis.
Advise females of reproductive potential to avoid becoming pregnant while being treated with Kyprolis.
Advise males of reproductive potential to avoid fathering a child while being treated with Kyprolis. Advise
women who use Kyprolis during pregnancy or become pregnant during treatment with Kyprolis of the
potential hazard to the fetus.
6. ADVERSE REACTIONS
The following adverse reactions have been discussed above and can be found in the Warnings and
Precautions section of the prescribing information. They include Cardiac Toxicities, Acute Renal Failure,
TLS, Pulmonary Toxicity, Pulmonary Hypertension, Dyspnea, Hypertension, Venous Thrombosis,
Infusion Reactions, Hemorrhage, Thrombocytopenia, Hepatic Toxicity and Hepatic Failure, Thrombotic
Microangiopathy, PRES, and Increased Fatal and Serious Toxicities in Combination with Melphalan and
Prednisone in Newly Diagnosed Transplant-Ineligible Patients.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug, and
may not reflect the rates observed in medical practice.
Safety Experience with Kyprolis in Combination with Lenalidomide and Dexamethasone in Patients with
Multiple Myeloma
The safety of Kyprolis in combination with lenalidomide and dexamethasone (KRd) was evaluated in an
open-label randomized study in patients with relapsed multiple myeloma. The median number of cycles
initiated was 22 cycles for the KRd arm and 14 cycles for the Rd arm.
Deaths due to adverse reactions within 30 days of the last dose of any therapy in the KRd arm occurred in
27/392 (7%) patients compared with 27/389 (7%) patients who died due to adverse reactions within 30
days of the last dose of any Rd therapy. The most common cause of deaths occurring in patients (%) in the
two arms (KRd versus Rd) included cardiac 10 (3%) versus 7 (2%), infection 9 (2%) versus 10 (3%), renal
0 (0%) versus 1 (< 1%), and other adverse reactions 9 (2%) versus 10 (3%). Serious adverse reactions
were reported in 60% of the patients in the KRd arm and 54% of the patients in the Rd arm. The most
common serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia
(14% vs. 11%), respiratory tract infection (4% vs. 1.5%), pyrexia (4% vs. 2%), and pulmonary embolism (3%
vs. 2%). Discontinuation due to any adverse reaction occurred in 26% in the KRd arm versus 25% in the
Rd arm. Adverse reactions leading to discontinuation of Kyprolis occurred in 12% of patients and the most
common reactions included pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract
infection (0.8%).
Most Common Adverse Reactions (≥ 10% in the KRd Arm)
Occurring in Cycles 1-12 (20/27 mg/m2 Regimen in Combination
with Lenalidomide and Dexamethasone)
KRd Arm
(N = 392), n (%)
Adverse Reactions by Body System

Any Grade

Rd Arm
(N = 389), n (%)

≥ Grade 3

Any Grade

≥ Grade 3

Blood and Lymphatic System Disorders
Anemia

138 (35)

53 (14)

127 (33)

47 (12)

Neutropenia

124 (32)

104 (27)

115 (30)

89 (23)

Thrombocytopenia

100 (26)

58 (15)

75 (19)

39 (10)

Diarrhea

115 (29)

7 (2)

105 (27)

12 (3)

Constipation

68 (17)

53 (14)

1 (0)

Nausea

60 (15)

1 (0)

39 (10)

3 (1)

Gastrointestinal Disorders

General Disorders and Administration Site Conditions
Fatigue

109 (28)

21 (5)

104 (27)

20 (5)

Pyrexia

93 (24)

5 (1)

64 (17)

1 (0)

Edema peripheral

63 (16)

2 (1)

57 (15)

2 (1)

Asthenia

53 (14)

11 (3)

46 (12)

7 (2)

85 (22)

7 (2)

52 (13)

3 (1)

Infections and Infestations
Upper respiratory tract infection

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 3