Summary Basis of Decision for Kyprolis

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Kyprolis is located below.

Recent Activity for Kyprolis

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Kyprolis

Updated:

2011-11-02

The following table describes post-authorization activity for Kyprolis, a product which contains the medicinal ingredient carfilzomib. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Drug Identification Number (DIN):

DIN 02451034 – 60 mg/vial, carfilzomib, powder for solution, intravenous administration
DIN 02459930 – 10 mg/vial, carfilzomib, powder for solution, intravenous administration
DIN 02459949 – 30 mg/vial, carfilzomib, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
SNDS # 2458732020-10-30Issued NOC
2021-06-02		Submission filed as a Level I – Supplement to make updates to the manufacturing process of the drug product. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 2371962020-03-17Issued NOC
2021-01-29		Submission filed as a Level I – Supplement for a new indication for Kyprolis. The indication authorized was for use in combination with dexamethasone and daratumumab for the treatment of patients with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 2337232019-11-21Issued NOL
2020-02-25		Submission filed as a Level II (90 day) Notifiable Change to update the Product Monograph to reflect revisions in the company core data sheet. As a result of the NC, additions were made to the Warnings and Precautions and Adverse Reactions sections and Part III: Patient Medication Information of the Product Monograph. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 2302892019-07-31Issued NOC
2020-02-06		Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the drug substance. There were no changes to the approved drug substance specifications or to the quality of the drug product. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 2205902018-10-01Issued NOC
2019-09-06		Submission filed as a Level I – Supplement to add a once-weekly dosing regimen for Kyprolis in combination with dexamethasone for the currently authorized indication (treatment of patients with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy). The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 2261352019-03-26Issued NOL
2019-07-02		Submission filed as a Level II (90 day) Notifiable Change to update the Product Monograph to reflect revisions in the company core data sheet. As a result of the NC, additions were made to the Adverse Reactions section and Part III: Patient Medication Information of the Product Monograph. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 2129832018-01-19Issued NOC
2019-01-18		Submission filed as a Level I – Supplement to update the Product Monograph with clinical trial results. The submission was reviewed and considered acceptable. As a result of the SNDS, additions were made to the Warnings and Precautions and Adverse Reactions sections and Part III: Patient Medication Information of the Product Monograph. An NOC was issued.
SNDS # 2150102018-03-29Issued NOC
2018-10-25		Submission filed as a Level I – Supplement for the approval of an alternate manufacturing site of the drug product. Drug product manufactured at the new site is comparable to product manufactured at the current site. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 2185962018-07-25Issued NOL
2018-10-19		Submission filed as a Level II (90 day) Notifiable Change to update the Product Monograph to reflect revisions in the company core data sheet. As a result of the NC, additions were made to the Warnings and Precautions section and Part III: Patient Medication Information of the Product Monograph. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 2082962017-08-09Issued NOC
2018-06-08		Submission filed as a Level I – Supplement to update the Product Monograph with clinical trial results. The submission was reviewed and considered acceptable. As a result of the SNDS, additions were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the Product Monograph (PM), and corresponding changes were made to the PM Part III: Patient Medication Information. An NOC was issued.
SNDS # 1973432016-08-02Issued NOC
2017-07-07		Submission filed as a Level I – Supplement to update the Product Monograph (PM) with data from studies evaluating the pharmacokinetics of carfilzomib in patients with renal or hepatic impairment. The information was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Dosage and Administration, and Action and Clinical Pharmacology sections of the PM. An NOC was issued.
Drug product (DIN 02459930) market notificationNot applicableDate of first sale:
2017-02-13		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DIN 02459949) market notificationNot applicableDate of first sale:
2017-02-06		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 1949992016-05-12Issued NOC
2016-12-20		Submission filed as a Level I – Supplement to add additional vial presentations containing 10 mg and 30 mg of carfilzomib. The data were reviewed and considered acceptable, and an NOC was issued. Two new DINs (02459930 and 02459949) were issued.
NDS # 1904342015-12-16Issued NOC
2016-11-22		Submission filed as a Level I – Supplement for a new indication for Kyprolis. The indication authorized was for use in combination with either lenalidomide and dexamethasone or dexamethasone alone for the treatment of patients with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy. A Regulatory Decision Summary was published.
NC # 1961372016-06-20Cancellation Letter Received
2016-06-29		Submission filed as a Level II (120 day) Notifiable Change to update the Product Monograph with clinical trial results. The proposed revisions exceeded the scope of a Notifiable Change. The submission was therefore cancelled administratively by the sponsor so as to be filed as an SNDS.
Drug product (DIN 02451034) market notificationNot applicableDate of first sale:
2016-02-11		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations
NDS # 1844792015-05-19Issued NOC
2016-01-15		Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Kyprolis

Date SBD issued: 2016-03-15

The following information relates to the new drug submission for Kyprolis.

Carfilzomib, 60 mg, powder for solution, intravenous

Drug Identification Number (DIN):

  • 02451034

Amgen Canada Inc.

New Drug Submission Control Number: 184479

On January 15, 2016, Health Canada issued a Notice of Compliance to Amgen Canada Inc. for the drug product Kyprolis.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Kyprolis is favourable for use in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy.

1 What was approved?

Kyprolis, an antineoplastic agent, was authorized for use in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy.

The safety and efficacy of Kyprolis when combined with lenalidomide and dexamethasone have not been established in patients with renal impairment (creatinine clearance [CrCL] <50 mL/min) or in patients who progressed during prior bortezomib therapy.

No overall differences in effectiveness of Kyprolis in combination with lenalidomide and dexamethasone were observed between younger (<65 years of age) and older (≥65 years of age) patients. Overall, the patient incidence of certain adverse events (including cardiac failure) in clinical trials was higher for patients who were ≥65 years of age compared to patients who were <65 years of age.

The safety and effectiveness of Kyprolis in pediatric patients have not been established. Kyprolis as a monotherapy did not show a benefit over an active comparator (corticosteroids and cyclophosphamide) in a Phase III trial in patients with relapsed and refractory multiple myeloma. There were no differences in overall survival or progression-free survival between the two arms. Kyprolis is not indicated as a monotherapy for the treatment of relapsed and refractory multiple myeloma.

Kyprolis is contraindicated for patients who are hypersensitive to Kyprolis or to any ingredient in the formulation or component of the container. Kyprolis was approved for use when combined with lenalidomide and dexamethasone under the conditions stated in the Kyprolis Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Kyprolis (60 mg carfilzomib) is presented as a powder for solution for intravenous infusion. In addition to the medicinal ingredient, the powder contains anhydrous citric acid, sodium hydroxide, and sulfobutylether beta-cyclodextrin.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Kyprolis Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Kyprolis approved?

Health Canada considers that the benefit/risk profile of Kyprolis in combination with lenalidomide and dexamethasone is favourable for the treatment of patients with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy.

Multiple myeloma, an incurable and fatal clonal neoplastic proliferation of plasma cells in the bone marrow and of monoclonal immunoglobulins (M-proteins) in the blood or urine, is the second most common lymphoid malignancy worldwide. Multiple myeloma is a disease of older adults, with a median age at diagnosis of 70 years, and occurs slightly more often in males than in females. Bony involvement by the malignant cells results in anemia, bone pain, osteopenia, fractures, hypercalcemia, and neurologic disease from radiculopathies or cord compression. Important complications include infections (specifically pneumonia), renal failure, and cardiac events which are among the primary causes of early mortality in multiple myeloma patients.

Lenalidomide (Revlimid) plus dexamethasone is a standard of care for multiple myeloma patients who have received at least one prior line of therapy. The safety and efficacy of adding Kyprolis, an irreversible inhibitor of the proteaseome, to this regimen was determined in a pivotal Phase III trial (the ASPIRE trial). The ASPIRE trial enrolled 792 patients with relapsed multiple myeloma who had received between 1 to 3 prior lines of therapy. Patients were randomized 1:1 to receive Kyprolis plus lenalidomide and dexamethasone (KRd) or lenalidomide and dexamethasone alone (Rd). In the KRd arm, Kyprolis was administered for a maximum of 18 cycles unless discontinued early for disease progression or unacceptable toxicity. In both the KRd and Rd arms, lenalidomide and dexamethasone administration could continue until disease progression or unacceptable toxicity.

The primary endpoint was progression-free survival (PFS) determined by an Independent Review Committee (IRC) using standard objective International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria. Key secondary efficacy endpoints included overall survival (OS), overall response rates (ORR), and Quality of Life (QoL).

Patients receiving KRd had improved PFS compared to patients treated with Rd (Hazard Ration [HR] = 0.69, with 1-sided p-value <0.0001), representing a 31% reduction in the risk of disease progression or death. The median PFS was 26.3 months in the KRd arm compared to 17.6 months in the Rd arm. The PFS benefit of KRd over Rd was observed consistently in all subgroups. There were also more responses (87.1% versus [vs.] 66.7%, respectively) in patients treated with KRd, including more complete responses (31.8% vs. 9.4%, respectively). The interim overall survival results did not meet the protocol-specified early stopping boundary for statistical significance.

Approximately 20-40% of multiple myeloma patients have significant renal impairment as defined by creatinine clearance (CrCL) <50 mL/min. These patients were excluded from the ASPIRE trial as were patients who progressed during prior therapy with a bortezomib-containing regimen. Therefore, there is more uncertainty as to the effectiveness of the KRd regimen in these patients when compared to Rd alone. This information is included in the Indications and Clinical Use section of the Product Monograph.

In the ASPIRE trial, which included 392 patients in the KRd arm, the most common adverse reactions (>20%), included anemia, diarrhea, neutropenia, fatigue, thrombocytopenia, cough, pyrexia, upper respiratory tract infection, hypokalemia, muscle spasms, peripheral edema, nasopharyngitis and constipation. The most common serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (5.6 [vs.] 4.4%), pulmonary embolism (2.6% vs. 1.8%), deep vein thrombosis (2.3% vs. 1.5%), and febrile neutropenia (2.0% vs. 0.8%). The most common adverse events leading to discontinuation of Kyprolis included pneumonia (1%), myocardial infarction (0.8%) and upper respiratory tract infection (0.8%).

Other significant adverse events (AEs) included infusion reactions, tumour lysis syndrome, hypertension, thrombocytopenia and acute renal failure. Renal failure was reported more frequently in patients treated with KRd vs. Rd (8.4% vs. 7.2%); however, the extent of renal toxicity may be underrepresented since, as discussed above, patients with renal impairment were excluded from the ASPIRE trial.

The data submitted in support of this New Drug Submission indicate that Kyprolis has an acceptable safety profile as part of a triple combination therapy. The Product Monograph is the primary risk management strategy to manage the risks associated with Kyprolis and provides the necessary warnings pertaining to the AEs reported in clinical trials and in the post-marketing setting. The Product Monograph also recommends appropriate dose adjustments (reductions / interruptions) to manage side effects and, when necessary, provides recommendations for permanent discontinuation of Kyprolis.

The identified safety concerns include the following serious AEs: a) cardiac toxicities, b) pulmonary toxicities, c) hepatic failure, d) thrombotic microangiopathy, e) posterior reversible encephalopathy syndrome (PRES), f) hemorrhage and g) venous thromboembolism. All of these safety concerns are listed in a Serious Warnings and Precautions Box in the Kyprolis Product Monograph, in addition to the instruction that Kyprolis should be administered under the supervision of a physician experienced in the use of anticancer agents. Due to the risk of thrombosis in patients receiving lenalidomide, which is further increased by the addition of Kyprolis, it is recommended that patients receive antithrombotic therapy during treatment with KRd. The choice of antithrombotic agent used is to be based on an assessment of the patient's underlying risks and clinical status.

A Risk Management Plan (RMP) for Kyprolis was submitted by Amgen Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Kyprolis has been deemed acceptable.

Overall, the benefits of Kyprolis combination therapy observed in the pivotal trial are substantial and are considered to outweigh the potential risks. Kyprolis has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Kyprolis Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Kyprolis?

The drug submission for Kyprolis was reviewed under the Priority Review Policy. Kyprolis in combination with lenalidomide and dexamethasone demonstrated a significant increase in effectiveness with an improved benefit/risk profile compared to an existing therapy for relapsed multiple myeloma, a condition that is not adequately managed by a drug marketed in Canada.

Submission Milestones: Kyprolis

Submission MilestoneDate
Pre-submission meeting:2015-05-05
Request for priority status
Filed:2015-02-13
Approval issued by Director, Bureau of Metabolism, Oncology and Reproductive Sciences:2015-03-16
Submission filed:2015-05-19
Screening
Screening Deficiency Notice issued:2015-06-15
Response filed:2015-06-29
Screening Acceptance Letter issued:2015-07-21
Review
Quality Evaluation complete:2016-01-11
Clinical Evaluation complete:2016-01-15
Labelling Review complete:2016-01-14
Notice of Compliance issued by Director General:2016-01-15

The Canadian regulatory decision on the non-clinical and clinical pharmacology review of Kyprolis was based on the United States Food and Drug Administration (FDA) review, referring to the data filed in Canada as necessary. The foreign review completed by the European Union's centralized procedure European Medicines Agency (EMA) was used as an added reference. The Canadian regulatory decision on the clinical safety and efficacy review was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure EMA and the United States FDA were used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Kyprolis?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Kyprolis is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Kyprolis (carfilzomib) is an irreversible proteasome inhibitor that has demonstrated anti-proliferative and pro-apoptotic activities in non-clinical models. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors. In vitro, carfilzomib was found to have minimal inhibition against a panel of twenty-one non-proteasomal proteases.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Kyprolis for the recommended indication.

Special Populations

Based on the mechanism of action and toxicology studies, Kyprolis can cause fetal harm when administered to pregnant women. The relevant toxicology studies and the recommendation for females of reproductive potential to avoid becoming pregnant while being treated with Kyprolis is detailed in the Product Monograph.

Kyprolis is associated with an increased risk of thrombosis and it also is not known if carfilzomib will reduce the efficacy of oral contraceptives (due to drug-drug interactions). Therefore, the concomitant use of Kyprolis with oral contraceptives or hormonal methods of contraception associated with a risk of thrombosis should be carefully considered and be based on an individual benefit-risk assessment.

The impact of hepatic impairment on the safety, efficacy and pharmacokinetics of Kyprolis has not been established. One clinical study reported that carfilzomib or its metabolites were not appreciably excreted in the bile; however, there were limitations of this study and therefore the impact of hepatic impairment on the pharmacokinetics, efficacy and safety of carfilzomib and its metabolites is not known.

A renal impairment study was conducted in multiple myeloma patients receiving a Kyprolis dose of 15 mg/m2. Although renal impairment did not have any appreciable effect on the pharmacokinetics of carfilizomib, there was an increase in the longer lived M14 metabolite whose concentrations increased with the extent of renal impairment. The biological activities of this metabolite are not known.

QT Prolongation

Cases of QT interval prolongation have been reported in patients receiving Kyprolis in clinical studies, and an effect of Kyprolis on QT interval cannot be excluded. In an open label, uncontrolled trial in cancer patients receiving Kyprolis, statistically significant QTcF increases from baseline were observed at 20 min and 1 h post-dosing on Day 1, with a maximum mean change from baseline of 5.5 ms (90% Confidence Interval [CI] 2.7, 8.3) at 1 h, whilst on Day 15, statistically significant mean increases from baseline were observed from 2-5 min to 2 h post-dosing, with a maximum mean increase from baseline of 9.8 ms (90% CI 5.0, 14.5) at 1 h post-dosing.

In a pooled analyses from two clinical studies of 154 patients with advanced malignancies, the effect of Kyprolis on cardiac repolarization based analysis of concentration-QTc relationships showed no clear signal of any dose-related effect. The upper bound of the one-sided 95% CI for predicted effect on QTcF at maximum concentration (Cmax) was 4.8 ms.

Overall Analysis of Clinical Pharmacology

Many of the toxicological effects of carfilzomib observed in animals (cardiac, pulmonary, renal, hepatic and gastrointestinal) were reported in clinical studies following administration of Kyprolis to multiple myeloma patients. The extent of toxicity was greater in animals when normalized to human clinical doses. The reason for increased toxicities of animals compared to humans is not known but may reflect an overall greater sensitivity to proteasome inhibition as similar results were reported for the first in class proteasome inhibitor bortezomib.

For further details, please refer to the Kyprolis Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Kyprolis in combination with lenalidomide and dexamethasone in relapsed multiple myeloma patients was evaluated in a pivotal Phase III, randomized, open-label trial named ASPIRE. In this trial, patients were randomized 1:1 (396 patients in each arm) to receive either Kyprolis, lenalidomide and dexamethasone (the "KRd" regimen) or lenalidomide and dexamethasone (the comparator "Rd" regimen) alone. Currently, Rd is an important standard of care treatment for patients with relapsed multiple myeloma.

In the KRd arm, Kyprolis was evaluated at a starting dose of 20 mg/m2, which was increased to 27 mg/m2 on Cycle 1, Day 8 onward. Kyprolis was administered as a 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle for Cycle 1 through 12. Kyprolis was dosed on Days 1, 2, 15, and 16 of each 28-day cycle from Cycle 13 through 18. Dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 and 22 of each cycle. Lenalidomide was given 25 mg orally on Days 1 to 21 of each 28-day cycle. The Rd treatment arm had the same regimen for lenalidomide and dexamethasone as the KRd treatment arm. Kyprolis was administered for a maximum of 18 cycles unless discontinued early for disease progression or unacceptable toxicity. Lenalidomide and dexamethasone administration could continue until progression or unacceptable toxicity.

The primary efficacy endpoint was progression-free survival (PFS) as determined by an Independent Review Committee (IRC) using standard objective International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria. Key secondary efficacy endpoints included overall survival (OS) and overall response rates (ORR).

Patients in the KRd arm demonstrated improved PFS compared with those in the Rd arm (Hazard Ratio [HR] = 0.69, 1-sided p value <0.0001). This represents a 31% reduction in the risk of disease progression or death. The median PFS was 26.3 months in the KRd arm versus (vs.) 17.6 months in the lenalidomide and dexamethasone (Rd) arm. The PFS benefit of KRd was observed consistently in all subgroups including those defined according to age, cytogenetic risk, and number of prior lines of therapy.

An interim overall survival (OS) analysis was conducted at the time of the final PFS analysis. There was a trend for an OS benefit in patients enrolled in the KRd vs. the Rd arm (HR: 0.79; 95% CI: 0.63, 0.99) but this did not cross the pre-specified early stopping boundary (one-sided p value = 0.0051). The study is ongoing for OS.

Overall response rates were higher in the KRd vs. the Rd arm (87.1% vs. 66.7%; one-sided p value <0.0001) with complete responses (CR) and stringent CR (sCR) reported in 31.8% and 9.4% of patients, respectively. Patients treated with KRd reported improved global health status, with higher Global Health Status/Quality of Live (QoL) scores compared with Rd over 18 cycles of treatment (p value = 0.0001) measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnnaire (QLQ) C30, an instrument validated in multiple myeloma.

Of note, patients with renal impairment (creatinine clearance [CrCL] <50 mL/min) including patients with moderate (CrCL = 30-50 mL/min) and severe (CrCL <30 mL/min) renal dysfunction were excluded from the ASPIRE trial. These patients comprise between 20-40% of multiple myeloma patients at diagnosis as renal impairment is often associated with this disease. Patients were also excluded from the trial if their disease progressed during prior treatment with bortezomib. The indication statement in the Product Monograph addresses the additional uncertainty of Kyprolis in combination with lenalidomide and dexamethasone in these patients.

Indication

The indication sought by the sponsor was as follows:

Kyprolis in combination with lenalidomide and dexamethasone is indicated for the treatment of patients with multiple myeloma who have received at least one prior therapy.

Upon review, it was determined that the indication did not accurately reflect the patients enrolled into the ASPIRE trial. Patients enrolled in this trial had received 1 to 3 prior lines of therapy and 27.8% of patients in the KRd arm and 30.1% of patients in the Rd arm were refractory to their most recent line of therapy. Patients were excluded from the pivotal trial if they had a CrCL less than 50 mL/min; this was a significant exclusion as approximately 20-40% of patients with multiple myeloma have this degree of renal dysfunction. Patients were also excluded if they had progressed during treatment on a prior bortezomib containing regimen.

To ensure the safe and effective use of the product, Health Canada recommended the following indication:

Kyprolis in combination with lenalidomide and dexamethasone is indicated for the treatment of patients with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy.

The clinical effectiveness of Kyprolis when combined with lenalidomide and dexamethasone (KRd) has not been established in patients with renal impairment (creatinine clearance [CrCL] <50 mL/min) or in patients who progressed during treatment with prior bortezomib therapy. These patients were excluded from the pivotal trial.

Overall Analysis of Efficacy

The efficacy data from the ASPIRE trial support the market authorization of Kyprolis in combination with lenalidomide and dexamethasone with an acceptable safety profile.  However, important exclusions were noted that were mandated in the protocol and the patients enrolled in ASPIRE do not represent all patients with relapsed multiple myeloma who may receive the KRd regimen in the post-market setting. Importantly, patients with renal impairment (creatinine clearance [CrCL] <50 mL/min) including patients with moderate (CrCL = 30-50 mL/min) and severe (<30 mL/min) renal dysfunction were excluded from the trial. These patients comprise between 20-40% of multiple myeloma patients at diagnosis as renal impairment is often associated with this disease. The reason for excluding these patients was to avoid reducing the starting dose of lenalidomide, which would be required for this drug due to its increased exposure in patients with renal impairment. While excluding patients with renal impairment allowed consistent dosing at enrollment (for an already complicated dosing schedule), there is uncertainty as to the effectiveness of KRd in these patients. Only two patients with CrCL <50mL/min were randomized to the KRd arm and at the time of the first Kyprolis dose, only 4.8% (19/396) of patients had a CrCL <50 mL/min.

The Product Monograph includes information discussing the uncertainty of the clinical effectiveness of Kyprolis in patients with renal impairment or in patients who progressed during treatment with a prior bortezomib-containing regimen. The indication statement also includes the word relapsed (to exclude primary refractory patients) and specifies patients should have had between 1 to 3 prior therapies to be eligible for treatment with Kyprolis.

Kyprolis as a monotherapy did not show benefit over an active comparator (corticosteroids and cyclophosphamide) in a Phase III trial (FOCUS trial) in patients with relapsed and refractory multiple myeloma. In this study, there were no differences in OS or PFS between the two arms, and therefore it is not indicated as a monotherapy for the treatment of relapsed and refractory multiple myeloma. Since Kyprolis monotherapy is approved in other jurisdictions and prescribers in Canada may wish to use it off-label to treat a more refractory patient population, Health Canada considered it important to provide these results in the form of a warning in the Product Monograph.

For more information, refer to the Kyprolis Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Kyprolis was primarily evaluated in the pivotal trial (the ASPIRE trial) described in the Clinical Efficacy section.

The safety profile of Kyprolis in combination with lenalidomide and dexamethasone (the KRd regimen) is considered manageable for patients with relapsed multiple myeloma. Serious events associated with this regimen include: a) cardiac toxicities, b) pulmonary toxicities, c) hepatic failure, d) thrombotic microangiopathy, e) posterior reversible encephalopathy syndrome (PRES), f) hemorrhage, and g) venous thrombosis.

New or worsening cardiac failure (for example, congestive cardiac failure, pulmonary edema, decreased ejection fraction) and myocardial ischemia and infarction have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration and fatal outcomes have been reported with cardiac failure and myocardial infarction. In the ASPIRE trial, the incidence of cardiac failure events in the KRd and Rd arms were 6.4% and 4.1%, respectively, and the incidence of myocardial infarction events was 3.3% vs 1.3%, respectively. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina or arrhythmias uncontrolled by mediations were not eligible for enrollment in Kyprolis clinical trials. Given the exclusion of these patients from clinical trials and the older age associated with multiple myeloma patients it is possible that there will be more cardiac-related events associated with the KRd regimen in the post-marketing setting compared to those observed in clinical trials. Pericarditis is listed as a post-market AE with Kyprolis therapy but it is not included in the Warnings and Precautions section of the Product Monograph as there is insufficient evidence at this time to establish a role for Kyprolis. The sponsor will continue to monitor for this and other events.

Patients enrolled to either arm in the ASPIRE trial were required to have thromboprophylaxis therapy (for example, aspirin) during study treatment, primarily due to the risk of blood clots in patients receiving lenalidomide. Despite thromboprophylactic therapy, 15.3% of patients receiving KRd had a venous thromboembolic event, which was higher than in the lenalidomide and dexamethasone (Rd) treatment arm (9.0%) suggesting that Kyprolis increases the risk of a thromboembolic event in patients receiving lenalidomide. Thromboprophylactic therapy is recommended in patients treated with KRd and the choice of antithrombotic agent should be based on an assessment of the patient's underlying risks and clinical status.

Other significant adverse events (AEs) included infusion reactions, tumour lysis syndrome, hypertension, thrombocytopenia and acute renal failure. Renal failure was reported more frequently in patients treated with KRd vs. Rd (8.4% vs. 7.2%); however, the extent of renal toxicity may be underrepresented since, as discussed above, patients with renal impairment were excluded from the ASPIRE trial.

Overall, most adverse events in patients treated with the Kyprolis were manageable by dose modifications (interruptions and reductions). Discontinuation of study treatment due to an adverse event occurred in 13.8% of patients in the KRd arm and 16.7% in the Rd arm. Adverse events leading to discontinuation of study drug that occurred in ≥3 patients in either study arm were pneumonia, myocardial infarction, and thrombocytopenia. There were more adverse events with a fatal outcome in the KRd arm compared to the Rd arm (6.9% vs. 5.4%), including 3 versus 0 deaths due to myocardial infarction, respectively. The median exposure to Kyprolis was 18 treatment cycles (1.4 years), the maximum allowed by study protocol, despite the recommendation in the Product Monograph that treatment may be continued until disease progression or until unacceptable toxicity occurs.

The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Kyprolis: cardiac toxicities, pulmonary toxicities, hepatic failure, thrombotic microangiopathy, posterior reversible encephalopathy syndrome (PRES), hemorrhage, and venous thrombosis. In addition, as indicated in the Serious Warnings and Precautions Box, Kyprolis should be administered under the supervision of a physician experienced in the use of anticancer agents. Other important adverse events include infusion reactions (requiring steroid pre-treatment and adequate hydration before dosing), tumour lysis syndrome, acute renal failure, hypertension (including some reports of hypertensive crisis), and thrombocytopenia.

Appropriate warnings and precautions are in place in the approved Kyprolis Product Monograph to address the identified safety concerns.

For more information, refer to the Kyprolis Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The results of the non-clinical studies as well as the potential risks to humans have been included in the Kyprolis Product Monograph. In view of the intended use of Kyprolis, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

Animals exposed to carfilzomib had significant toxicities at doses lower than are achieved clinically in humans. The reasons for the increased sensitivity of animals are not known but it may be directly related to proteasome inhibition since similar findings have been reported with bortezomib (Velcade). Carfilzomib caused significant cardiac, pulmonary, liver and renal toxicities in rats and monkeys, which have translated to findings in the clinical setting. Carfilzomib can cause fetal harm supporting the recommendations to avoid using Kyprolis in women who are or who may become pregnant or in men who may father a child. It is also recommended not to breastfeed while receiving Kyprolis as it is not known if carfilzomib is passed through the mother's milk. 

Carcinogenicity and fertility studies have not been conducted with Kyprolis. In vitro, carfilzomib was clastogenic but not mutagenic.

Appropriate warnings and precautionary measures are in place in the Kyprolis Product Monograph to address the identified safety concerns.

For more information, refer to the Kyprolis Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Kyprolis has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months when maintained within the secondary packaging (a cardboard carton) to protect from light is acceptable.

Proposed limits of drug-related impurities are considered adequately qualified (that is [i.e.] within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

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