Safety: Kd once weekly

Safety: Kd once weekly study

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Safety experience
Safety profile
Median treatment duration
Frail-subgroup safety profile

The International Myeloma Society recommends modifying treatment by considering a once-weekly regimen for appropriate RRMM patients to reduce the number of hospital/clinic visits during the COVID-19 pandemic.⁵

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Safety experience

Overall safety was comparable across treatment arms¹

Discontinuation due to adverse reactions^1,2

The most common adverse event leading to discontinuation of either KYPROLIS^® or dexamethasone was acute kidney injury.¹

Safety experience with Kd 70 mg/m² once weekly vs Kd 27 mg/m² twice weekly^1,2

Deaths due to adverse reactions within 30 days of the last study treatment occurred in 9% of patients in the Kd 70 mg/m² once weekly arm compared with 8% of patients in the Kd 27 mg/m² twice weekly arm¹
The most frequent fatal adverse reactions occurring in patients in the 2 arms included (n, %): sepsis (2, < 1% vs 2, < 1%), septic shock (2, < 1% vs 1, < 1%), and infection (2, < 1% vs 0, 0%)¹
Dose reductions due to adverse reactions were reported in 11% of patients in the Kd once weekly arm vs 5% in the Kd twice weekly arm²

*Kd 27 mg/m² is not an FDA-approved dose for KYPROLIS^®.¹

Kd = KYPROLIS^®+dexamethasone; RRMM = relapsed or refractory multiple myeloma.

Safety profile

Additional safety and clinical considerations²

The once-weekly dose of Kd 70 mg/m² did not reveal any new cardiovascular safety risks¹
The overall incidence of cardiac failure events was 3.8% in the Kd 70 mg/m² once weekly arm versus 5.1% in the Kd 27 mg/m² twice weekly arm¹
The frequency of Grade ≥ 3 cardiac failure events was observed in 3% of Kd 70 mg/m² once weekly patients²
No new cardiac safety signals were seen in the Kd 70 mg/m² once-weekly arm^1,2

Select adverse reactions of interest^1,2

	Kd 70 mg/m² once weekly (n = 238), n (%)		Kd 27 mg/m² twice weekly* (n = 235), n (%)
	All grades	Grade ≥ 3	All grades	Grade ≥ 3
Peripheral neuropathy	10 (4)	0 (0)	16 (7)	1 (< 1)
Acute renal failure	17 (7)	9 (4)	16 (7)	13 (6)
Cardiac failure^1,2	9 (3.8)	7 (3)	12 (5.1)	10 (4)
Ischemic heart disease	4 (2)	2 (1)	3 (1)	2 (1)
Pulmonary hypertension	4 (2)	0 (0)	3 (1)	1 (< 1)

Most common adverse reactions occurring in ≥ 10% of patients in either treatment arm¹

Adverse reactions by body system	Kd 70 mg/m² once weekly (n = 238), n (%)		Kd 27 mg/m² twice weekly* (n = 235), n (%)
	Any grade	Grade ≥ 3	Any grade	Grade ≥ 3
Blood and lymphatic system disorders
Anemia^†	64 (27)	42 (18)	76 (32)	42 (18)
Thrombocytopenia^‡	53 (22)	26 (11)	41 (17)	27 (12)
Neutropenia^§	30 (13)	21 (9)	27 (12)	17 (7)
Gastrointestinal disorders
Diarrhea	44 (19)	2 (1)	47 (20)	3 (1)
Nausea	34 (14)	1 (< 1)	26 (11)	2 (1)
General disorders and administration site conditions
Pyrexia	55 (23)	2 (1)	38 (16)	4 (2)
Fatigue	48 (20)	11 (5)	47 (20)	5 (2)
Asthenia	24 (10)	3 (1)	25 (11)	2 (1)
Peripheral edema	18 (8)	0 (0)	25 (11)	2 (1)
Infections and infestations
Respiratory tract infection**	70 (29)	7 (3)	79 (34)	7 (3)
Pneumonia	28 (12)	24 (10)	20 (9)	16 (7)
Bronchitis	27 (11)	2 (1)	25 (11)	5 (2)
Musculoskeletal and connective tissue disorders
Back pain	28 (12)	2 (1)	28 (12)	4 (2)
Nervous system disorders
Headache	25 (11)	1 (< 1)	23 (10)	1 (< 1)
Psychiatric disorders
Insomnia	35 (15)	2 (1)	47 (20)	0 (0)
Respiratory, thoracic, and mediastinal disorders
Cough^††	37 (16)	2 (1)	31 (13)	0 (0)
Dyspnea^‡‡	28 (12)	1 (< 1)	26 (11)	2 (1)
Vascular disorders
Hypertension^§§	51 (21)	13 (6)	48 (20)	12 (5)

*Kd 27 mg/m² is not an FDA-approved dose for KYPROLIS^®.¹

^†Anemia includes anemia, hematocrit decreased, and hemoglobin decreased.

^‡Thrombocytopenia includes platelet count decreased and thrombocytopenia.

^§Neutropenia includes neutrophil count decreased and neutropenia.

**Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection, and viral upper respiratory tract infection.

^††Cough includes cough and productive cough.

^‡‡Dyspnea includes dyspnea and dyspnea exertional.

^§§Hypertension includes hypertension and hypertensive crisis.

Kd = KYPROLIS^®+dexamethasone.

Median treatment duration

The median treatment duration was 38 weeks in the Kd 70 mg/m² once weekly arm vs 29 weeks in the Kd 27 mg/m² twice weekly arm¹^,*

Median treatment duration (Kd 70 mg/m² once weekly vs Kd 27 mg/m² twice weekly)^1,3

*Kd 27 mg/m² is not an FDA-approved dose for KYPROLIS^®.¹

Kd = KYPROLIS^® (carfilzomib)+dexamethasone.

Select frail-subgroup safety profile (Kd 70 mg/m² once weekly vs Kd 27 mg/m² twice weekly)⁴^,*

SELECT GRADE ≥ 3 TEAEs OF INTEREST

Select grade ≥ 3 TEAEs of interest, n	Kd 70 once weekly (n = 79)	Kd 27 twice weekly (n = 60)
Peripheral neuropathy	0	0
Acute renal failure	3	4
Cardiac failure	3	5
Ischemic heart disease	0	1
Pulmonary hypertension	0	1

DISCONTINUATION RATES DUE TO TEAEs

*Kd 27 mg/m² is not an FDA-approved dose for KYPROLIS^®.

Kd = KYPROLIS^®+dexamethasone; Kd 70 = Kd 70 mg/m²; Kd 27 = Kd 27 mg/m²; TEAE = treatment-emergent adverse event.

REFERENCES

1. KYPROLIS^® (carﬁlzomib) prescribing information, Onyx Pharmaceuticals Inc., an Amgen Inc. subsidiary. 2. Moreau P, Mateos M-V, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018;19:953-964. 3. Data on file, Amgen; 2018. 4. Mateos M, Ludwig H, Kumar S, et al. Safety and efficacy of once-weekly carfilzomib dosing in frail patients: a subgroup analysis from the phase 3 A.R.R.O.W. study. Poster presented at: 17th International Myeloma Workshop; September 2019; Boston, MA. 5. International Myeloma Society recommendations for the management of myeloma patients during the COVID-19 pandemic. International Myeloma Society website. https://cms.cws.net/content/beta.myelomasociety.org/files/IMS recommendations for Physicians Final.pdf. Accessed April 27, 2020.

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), 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 reactions 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 (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. Provide thromboprophylaxis for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
For patients using hormonal contraception associated with a risk of thrombosis, consider an alternative method of effective contraception during treatment.

Infusion-Related Reactions

Infusion-related 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-related reactions.

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.

Progressive Multifocal Leukoencephalopathy (PML)

Cases of PML, including fatal cases, have occurred. In addition to KYPROLIS, other contributary factors may include prior or concurrent use of immunosuppressive therapy. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue and initiate evaluation for PML including neurology consultation.

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 reactions 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.
Advise pregnant women of the potential risk to a fetus. Females of reproductive potential should use effective contraception during treatment with KYPROLIS and for 6 months following the final dose. Males of reproductive potential should use effective contraception during treatment with KYPROLIS and for 3 months following the final dose.

Adverse Reactions

The most common adverse reactions in the combination therapy trials: anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia.
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.

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), 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 reactions 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 (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. Provide thromboprophylaxis for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
For patients using hormonal contraception associated with a risk of thrombosis, consider an alternative method of effective contraception during treatment.

Infusion-Related Reactions

Infusion-related 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-related reactions.

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.

Progressive Multifocal Leukoencephalopathy (PML)

Cases of PML, including fatal cases, have occurred. In addition to KYPROLIS, other contributary factors may include prior or concurrent use of immunosuppressive therapy. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue and initiate evaluation for PML including neurology consultation.

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 reactions 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.
Advise pregnant women of the potential risk to a fetus. Females of reproductive potential should use effective contraception during treatment with KYPROLIS and for 6 months following the final dose. Males of reproductive potential should use effective contraception during treatment with KYPROLIS and for 3 months following the final dose.

Adverse Reactions

The most common adverse reactions in the combination therapy trials: anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia.
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.

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.

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