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| Carfilzomib (e.g., Kyprolis) | |
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| Description: |
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib exhibits antiproliferative and proapoptotic activity in solid and hematologic tumor cells in vitro. Carfilzomib is approved for the treatment of adult individuals with relapsed or refractory multiple myeloma (Kyprolis, 2020).
Multiple myeloma (MM) is characterized by the neoplastic proliferation of clonal plasma cells producing a monoclonal immunoglobulin. These clonal plasma cells proliferate in the bone marrow and often result in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. Conventional therapy is not curative, and most
individuals will ultimately progress and some will not respond to initial treatment (Rajkumar, 2020).
The National Comprehensive Cancer Network® (NCCN) includes additional off-label category 2A recommendations for the use of carfilzomib. Recommendations include use for primary treatment and treatment for relapsed or refractory multiple myeloma with various drug regimens. NCCN also provides 2A recommendations for use of carfilzomib for primary or relapsed or refractory
Waldenstrom’s macroglobulinemia in combination with rituximab (or rituximab biosimilar), and dexamethasone. Please refer to the NCCN guidelines for NCCN 1 and 2A recommendations.
Carfilzomib carries multiple warnings and precautions to consider before use including: cardiac toxicities, acute renal failure, tumor lysis syndrome, pulmonary toxicities, pulmonary hypertension, dyspnea, hypertension, venous thrombosis, infusion-related reactions, hemorrhage, thrombocytopenia, hepatic toxicity, hepatic failure, thrombotic microangiopathy, posterior reversible encephalopathy syndrome, progressive multifocal leukoencephalopathy, increase fatal and serious toxicities in combination with melphalan and prednisone in newly diagnosed transplant-ineligible
individuals and embryo-fetal toxicity (Kyprolis, 2020).
Regulatory Status
Carfilzomib (e.g., Kyprolis) was approved by the U.S. Food and Drug Administration (FDA) on July 20th, 2012. FDA labeling indications include use as a single agent for the treatment of adult
individuals with relapsed or refractory multiple myeloma who have received one or more line of therapy, or in combination with either lenalidomide plus dexamethasone, dexamethasone, or daratumumab plus dexamethasone.
On November 30, 2021, the U.S. Food and Drug Administration approved daratumumab and hyaluronidase-fihj in combination with carfilzomib and dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Prior Approval is required for Carfilzomib (e.g., Kyprolis).
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
INITIAL AND CONTINUATION APPROVAL will be for duration of the treatment course or 12 months (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.
Effective May 4, 2026
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
Carfilzomib (e.g., Kyprolis) meets member benefit certificate
Primary Coverage Criteria coverage criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts
without Primary Coverage Criteria, is considered Medically Necessary and is covered, when
ALL the following criteria are met:
FDA Labeled Indications
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication below with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”).
INITIAL APPROVAL:
CONTINUATION OF THERAPY:
Off-label Indications
The use of this drug for off-label indications not listed below is subject to policy 2000030.
INITIAL APPROVAL:
The following indications are covered when the individual meets the related NCCN category 1 or 2A recommendations specific to the indications below (e.g., histology, cancer staging, surgical status, mono- or combination therapy, and previous lines of therapy):
CONTINUATION OF THERAPY:
Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications. To view the most recent and complete version of the guideline or Compendium, go online to NCCN.org. Please note, NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
Carfilzomib (e.g., Kyprolis) for any indication or circumstance not described above, does not meet member benefit certificate
Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
For members with contracts without Primary Coverage Criteria, Carfilzomib (e.g., Kyprolis), for any indication or circumstance not described above, is considered
not Medically Necessary and is not covered or is
investigational. Not Medically Necessary or
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
POLICY GUIDELINES
Eastern Cooperative Oncology Group (ECOG) Performance
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
DOSAGE AND ADMINISTRATION
For FDA labeled indications, Carfilzomib (e.g., Kyprolis) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication below.
Note:
Doses may not exceed 154 mg IV (Per package insert, for individuals with a BSA greater than 2.2 square meters, dose of Carfilzomib (e.g., Kyprolis) should be based on a BSA of 2.2 square meters).
Refer to the Prescribing Information for more complete dosing information of Carfilzomib (e.g., Kyprolis) and dosing information for lenalidomide, dexamethasone, daratumumab and other agent dosing.
Carfilzomib (e.g., Kyprolis) is available as a powder for injection (10 mg, 30 mg and 60 mg).
Carfilzomib (e.g., Kyprolis) should be administered as an IV infusion by a healthcare professional.
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
Effective February 12, 2025 to May 3, 2026
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
Carfilzomib meets primary benefit certificate coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when
ALL the following criteria are met:
FDA Labeled Indications:
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
Off-label Indications:
For off-label indications, authorizations will not exceed
154 mg IV unless medical literature supports a higher dose.
Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications.
Policy Guidelines
Eastern Cooperative Oncology Group (ECOG) Performance
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines where applicable. For off-label indications, authorizations will not exceed
154 mg IV unless medical literature supports a higher dose.
Note:
Doses may not exceed 154 mg IV (Per package insert, for individuals with a BSA greater than 2.2 square meters, dose of carfilzomib should be based on a BSA of 2.2 square meters).
Refer to the Prescribing Information for more complete dosing information of carfilzomib and dosing information for lenalidomide, dexamethasone, daratumumab and other agent dosing.
Carfilzomib is available as a powder for injection (10 mg, 30 mg and 60 mg).
Carfilzomib should be administered as an IV infusion by a healthcare professional.
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Carfilzomib, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, carfilzomib, for any indication or circumstance not described above, is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective February 7, 2024 to February 11, 2025
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
Carfilzomib meets primary benefit certificate coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when
ALL the following criteria are met:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
Note:
Doses may not exceed 154 mg IV (Per package insert, for individuals with a BSA greater than 2.2 square meters, dose of carfilzomib should be based on a BSA of 2.2 square meters)
Refer to the Prescribing Information for more complete dosing information of carfilzomib and dosing information for lenalidomide, dexamethasone, daratumumab and other agent dosing.
Carfilzomib is available as a powder for injection (10 mg, 30 mg and 60 mg).
Carfilzomib should be administered as an IV infusion by a healthcare professional.
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Carfilzomib, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, carfilzomib, for any indication or circumstance not described above, is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective March 29, 2023 to February 6, 2024
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
Carfilzomib meets primary benefit certificate coverage criteria that there be scientific evidence of effectiveness in improving heath outcomes when
ALL of the following criteria are met:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
Note:
Doses may not exceed 154 mg IV (Per package insert, for patients with a BSA greater than 2.2 m2, dose of carfilzomib should be based on a BSA of 2.2 m2)
Refer to the Prescribing Information for more complete dosing information of carfilzomib and dosing information for lenalidomide, dexamethasone, daratumumab and other agent dosing.
Carfilzomib is available as a powder for injection (10 mg, 30 mg and 60 mg).
Carfilzomib should be administered as an IV infusion by a healthcare professional.
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Carfilzomib for any indication or circumstance other than those oulined above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of carfilzomib in any other condition than listed above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective February 16, 2023 to March 28, 2023
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
The use of carfilzomib meets primary benefit certificate coverage criteria that there be scientific evidence of effectiveness in improving heath outcomes when
ALL of the following criteria are met:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
Note:
Doses may not exceed 154 mg IV (Per package insert, for patients with a BSA greater than 2.2 m2, dose of carfilzomib should be based on a BSA of 2.2 m2)
Refer to the Prescribing Information for more complete dosing information of carfilzomib and dosing information for lenalidomide, dexamethasone, daratumumab and other agent dosing.
Carfilzomib is available as a powder for injection (10 mg, 30 mg and 60 mg).
Carfilzomib should be administered as an IV infusion by a healthcare professional.
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Carfilzomib for any indication or circumstance other than those oulined above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of carfilzomib in any other condition than listed above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective March 2, 2022 to February 15, 2023
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
The use of carfilzomib meets primary coverage criteria when
ALL of the following criteria are met:
3. Individual has an Eastern Cooperative Oncology Group (ECOG) Performance status 0-2 based on the following scale (FDA, 2021):
AND
4. Individual has been treated with no more than three regimens for multiple myeloma previously (FDA, 2021)
AND
5. Individual has not had a myocardial infarction within 4 months prior to initiation, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia (FDA, 2021)
AND
6. Individual has not had known moderate to severe persistent asthma within the past two years OR COPD with a FEV1 <50% of predicted normal (Quach, 2021)
AND
7. Individual is using for one of the following:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Note:
2. Carfilzomib in combination with dexamethasone.
3. Carfilzomib in combination with daratumumab and dexamethasone
or daratumumab and hyaluronidase-fihj and dexamethasone.
4. Carfilzomib monotherapy.
Carfilzomib is available as a powder for injection (10 mg, 30 mg and 60 mg).
Carfilzomib should be administered as an IV infusion by a healthcare professional.
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Carfilzomib does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than those outlined above.
For members with contracts without primary coverage criteria, the use of carfilzomib in any other condition than listed above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective May 1, 2021 to March 1, 2022
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
The use of carfilzomib meets primary coverage criteria when
ALL of the following criteria are met:
NCCN 1 and 2A recommendations in accordance with Coverage Policy #2000030.
Dosage and Administration
Note:
Carfilzomib is available as a powder for injection (10 mg, 30 mg and 60 mg).
Carfilzomib should be administered as an IV infusion by a healthcare professional.
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Carfilzomib does not meet member benefit certificate primary coverage criteria for any other indication.
For members with contracts without primary coverage criteria, the use of carfilzomib in any other condition than listed above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
Carfilzomib has been studied for relapsed or refractory multiple myeloma in several studies, alone and in various combinations described below.
In Combination with Lenalidomide and Dexamethasone for Relapsed or Refractory Multiple Myeloma
The efficacy of Kyprolis in combination with lenalidomide and dexamethasone was evaluated in the ASPIRE study. The ASPIRE study was a randomized, open-label, multicenter trial which evaluated the combination of Kyprolis with lenalidomide and dexamethasone (KRd) versus lenalidomide and dexamethasone alone (Rd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 lines of therapy. The 792 patients in ASPIRE were randomized 1:1 to the KRd or Rd arm. The demographics and baseline characteristics were well-balanced between the two arms. The primary endpoint was progression-free survival (PFS).
Pertinent patient exclusions from the trial include: refractory to bortezomib in the most recent regimen, refractory to lenalidomide and dexamethasone in the most recent regimen, not responding to any prior regimen, New York Heart Association Class III to IV congestive heart failure, or myocardial infarction within the last 4 months.
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.
Patients in the KRd arm demonstrated improved PFS compared with those in the Rd arm (HR = 0.69, with 2-sided P-value = 0.0001) as determined using standard International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria by an Independent Review Committee (IRC). The median PFS was 26.3 months in the KRd arm
versus 17.6 months in the Rd arm.
Median OS was 48.3 months (95% CI, 42.4 to 52.8 months) for KRd versus 40.4 months (95% CI, 33.6 to 44.4 months) for Rd (hazard ratio, 0.79; 95% CI, 0.67 to 0.95; one-sided
P = .0045). This was statistically significant for the KRd vs Rd group. In patients receiving one prior line of therapy, median OS was 11.4 months longer for KRd versus Rd; it was 6.5 months longer for KRd versus Rd among patients receiving
≥ two prior lines of therapy. Therefore, the KRd efficacy advantage was most pronounced at first relapse.
The median duration of response (DOR) was 28.6 months (95% CI: 24.9, 31.3) for the 345 patients achieving a response in the KRd arm and 21.2 months (95% CI: 16.7, 25.8) for the 264 patients achieving a response in the Rd arm. The median time to response was 1 month (range 1 to 14 months) in the KRd arm and 1 month (range 1 to 16 months) in the Rd arm.
In Combination with Dexamethasone for Relapsed or Refractory Multiple Myeloma
The efficacy of Kyprolis in combination with dexamethasone was evaluated in the ENDEAVOR trial. ENDEAVOR was a randomized, open-label, multicenter trial of Kyprolis and dexamethasone (Kd)
versus bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 lines of therapy. A total of 929 patients were enrolled and randomized (464 in the Kd arm; 465 in the Vd arm). Randomization was stratified by prior proteasome inhibitor therapy (yes versus no), prior lines of therapy (1
versus 2 or 3), current International Staging System stage (1 versus 2 or 3), and planned route of bortezomib administration. Pertinent patient exclusions included: less than partial response (PR) to all prior regimens or left-ventricular ejection fraction < 40% or other significant cardiac conditions.
This trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 56 mg/m2 on Cycle 1, Day 8 onward. Kyprolis was administered twice weekly as a 30-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle. In the Vd arm, bortezomib was dosed at 1.3 mg/m2 intravenously or subcutaneously on Days 1, 4, 8, and 11 of a 21-day cycle, and dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle. Of the 465 patients in the Vd arm, 381 received bortezomib subcutaneously. Treatment continued until disease progression or unacceptable toxicity.
The efficacy of Kyprolis was evaluated by PFS as determined by an IRC using IMWG response criteria. The trial showed a median PFS of 18.7 months in the Kd arm
versus 9.4 months in the Vd arm. This was statistically significant for the Kd arm vs the Vd arm. A significantly longer OS was observed in patients in the Kd arm compared to patients in the Vd arm. A 7.6-month OS benefit (median OS 47.6 months for Kd56 versus 40.0 for Vd, HR=0.79; p=0.01). The median DOR in subjects achieving PR or better was 21.3 months (95% CI: 21.3, not estimable) in the Kd arm and 10.4 months (95% CI: 9.3, 13.8) in the Vd arm. The median time to response was 1 month (range < 1 to 8 months) in both arms.
In Combination with Intravenous Daratumumab and Dexamethasone for Relapsed or Refractory Multiple Myeloma
The efficacy of Kyprolis in combination with daratumumab and dexamethasone (DKd) was evaluated in the CANDOR trial. CANDOR was a randomized, open-label, multicenter trial which evaluated the combination of Kyprolis 20/56 mg/m2 twice weekly with intravenous daratumumab and dexamethasone (DKd) versus Kyprolis 20/56 mg/m2 twice weekly and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy.
Pertinent patient exclusions included: known moderate or severe persistent asthma within the past 2 years, known chronic obstructive pulmonary disease (COPD) with a FEV1 < 50% of predicted normal, and active congestive heart failure. A total of 466 patients were randomized; 312 to the DKd arm and 154 to the Kd arm. Randomization was stratified by the ISS (stage 1 or 2 vs stage 3) at screening, prior proteasome inhibitor exposure (yes vs no), number of prior lines of therapy (1 vs ≥ 2), or prior cluster differentiation antigen 38 (CD38) antibody therapy (yes vs no).
Kyprolis was administered intravenously over 30 minutes at a dose of 20 mg/m2 in Cycle 1 on Days 1 and 2; at a dose of 56 mg/m2 in Cycle 1 on Days 8, 9, 15 and 16; and on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle thereafter. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15 and 16 and then 40 mg orally or intravenously on Day 22 of each 28-day cycle. In the DKd arm, daratumumab was administered intravenously at a dose of 8 mg/kg in Cycle 1 on Days 1 and 2. Thereafter, daratumumab was administered intravenously at a dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8 and 15 and 22 of Cycle 2; Days 1 and 15 of Cycles 3 to 6; and Day 1 for the remaining cycles or until disease progression. For patients >75 years on a reduced dexamethasone dose of 20 mg, the entire 20 mg dose was given as a daratumumab pre-infusion medication on days when daratumumab was administered. Dosing of dexamethasone was otherwise split across days when Kyprolis was administered in both study arms. Treatment was continued in both arms until disease progression or unacceptable toxicity.
Efficacy was assessed by an IRC evaluation of PFS using the IMWG response criteria. KdD significantly prolonged progression-free survival versus Kd. The regimen resulted in a 37% reduction in the risk of progression or death in patients with relapsed or refractory multiple myeloma treated with KdD (HR=0.630; 95% CI: 0.464, 0.854;
p=0.0014). The median PFS for patients treated with Kd alone was 15.8 months, while the median PFS for patients treated with KdD has not been reached by the cut-off date. The median duration of response has not been reached for the DKd arm and was 16.6 months (13.9, NE) for the Kd arm. The median (min, max) time to response was 1.0 (1, 14) months for the DKd arm and 1.0 (1, 10) months for the Kd arm.
Monotherapy for Relapsed or Refractory Multiple Myeloma
The efficacy of Kyprolis monotherapy was evaluated in an open-label clinical trial, FOCUS. Focus was a randomized, phase III, open-label, multicenter study that compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. The study did not meet its primary objective of carfilzomib superiority over control. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). This was statistically significant for the carfilzomib group (P=0.0305).
In combination with rituximab and dexamethasone for Waldenström’s macroglobulinemia
The efficacy of carfilzomib in combination with rituximab and dexamethasone for Waldenström’s macroglobulinemia was studied in a prospective, open-label, single stage, phase 2 study. Eligible patients were symptomatic, untreated with a proteasome inhibitor or rituximab, and had no more than 1 prior therapy. The primary endpoint was ORR. ORR was 87.1%. In a long term follow up the major response rate was 71%. The median PFS was 46 months. All patients are alive, and 14 patients remain in follow-up without a progression event.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2022. No new literature was identified that would prompt a change in the coverage statement.
March 2022 Update
A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression-free survival (PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorized by age. In the carfilzomib group, 103/396 patients were
≥70 years old, and in the control group, 115/396 patients were
≥70 years old. Median PFS for patients <70 years old was 28·6 months for the carfilzomib group versus 17·6 months for the control group [hazard ratio (HR), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the carfilzomib group versus 16·0 months for the control group (HR, 0·753). For patients <70 years the overall response rate (ORR) was 86·0% (carfilzomib group) and 66·9% (control group); for patients
≥70 years old the ORR was 90·3% (carfilzomib group) and 66·1% (control group). Within the carfilzomib group, grade
≥3 cardiovascular adverse events occurred more frequently among patients
≥70 years old compared with patients <70 years old. Carfilzomib-lenalidomide-dexamethasone has a favourable benefit-risk profile for patients with RMM, including elderly patients ≥70 years old. (Dimopoulos MA, Stewart AK, Masszi T,et.al., 2017)
The efficacy of Kyprolis with daratumumab and hyaluronidase-fihj plus dexamethasone (DKd) was evaluated in a single-arm cohort of PLEIADES, a multi-cohort, open-label trial. This cohort enrolled patients with relapsed or refractory multiple myeloma excluding patients with left ventricular ejection fraction (LVEF) less than 40%, myocardial infarction within 6 months, uncontrolled cardiac arrhythmia, or uncontrolled hypertension (systolic blood pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment). Patients received Kyprolis administered by IV infusion at a dose of 20 mg/m2 on Cycle 1 Day 1 and if a dose of 20 mg/m2 was tolerated Kyprolis was administered at a dose of 70 mg/m2 as a 30-minute IV infusion on Cycle 1 Day 8 and Day 15, and then Day 1, 8 and 15 of each cycle; daratumumab and hyaluronidase-fihj1,800 mg/30,000 units administered subcutaneously once weekly from Weeks 1 to 8, once every 2 weeks from Weeks 9 to 24 and once every 4 weeks starting with Week 25 until disease progression or unacceptable toxicity; and dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients
≥75 years or BMI <18.5). The major efficacy outcome measure was ORR.
A total of 66 patients received the DKd regimen. The median age was 61 years (range: 42, 84); 52% were male; 73% were White and 3% Black or African American; and 68% had ISS Stage I, 18% had ISS Stage II, and 14% had ISS Stage III disease. A total of 79% of patients had a prior ASCT; 91% of patients received a prior PI. All patients received 1 prior line of therapy with exposure to lenalidomide and 62% of patients were refractory to lenalidomide.
Efficacy results are summarized in Table 34. At a median follow-up of 9.2 months, the median duration of response had not been reached and an estimated 85.2% (95% CI: 72.5, 92.3) maintained response for at least 6 months and 82.5% (95% CI: 68.9, 90.6) maintained response for at least 9 months. (NCT03412565) (FDA, 2021)
2023 Update
The IKEMA study (Randomized, Open Label, Multicenter Study Assessing the Clinical Benefit of Isatuximab Combined With Carfilzomib [Kyprolis®] and Dexamethasone Versus Carfilzomib With Dexamethasone in Patients With Relapse and/or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines;
#NCT03275285) was a randomized, open-label, multicenter phase 3 study investigating isatuximab plus carfilzomib and dexamethasone (Isa-Kd) vs Kd in patients with relapsed multiple myeloma. This subanalysis analyzed the depth of response of Isa-Kd vs Kd. The primary end point was progression-free survival (PFS); secondary end points included overall response rate, very good partial response or better (≥VGPR) rate, complete response (CR) rate, and minimal residual disease (MRD) negativity rate (assessed in patients with
≥VGPR by next-generation sequencing at a 10-5 sensitivity level). At a median follow-up of 20.7 months, deeper responses were observed in the Isa-Kd arm vs the Kd arm, with ≥VGPR 72.6% vs 56.1% and CR of 39.7% vs 27.6%, respectively. MRD negativity occurred in 53 (29.6%) of 179 patients in the Isa-Kd arm vs 16 (13.0%) of 123 patients in the Kd arm, with 20.1% (Isa-Kd, 36 of 179 patients) vs 10.6% (Kd, 13 of 123 patients) reaching MRD-negative CR status. Achieving MRD negativity resulted in better PFS in both arms. A positive PFS treatment effect was seen with Isa-Kd in both MRD-negative patients (hazard ratio, 0.578; 95% CI, 0.052-6.405) and MRD-positive patients (hazard ratio, 0.670; 95% CI, 0.452-0.993). Exploratory analysis indicates that both current CR and MRD-negative CR rates are underestimated due to M-protein interference (potential adjusted CR rate, 45.8%; potential adjusted MRD-negative CR rate, 24.0%). In conclusion, there was a clinically meaningful improvement in depth of response with Isa-Kd. The CR rate in Isa-Kd was 39.7%. Mass spectrometry suggests that the potential adjusted CR rate could reach an unprecedented 45.8% of patients treated with Isa-Kd. (Martin T, Mikhael J, Hajek R, 2022)
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2024.
2025 Update
A prospective, randomised, open-label, active-controlled, phase 3 study included patients with relapsed or refractory multiple myeloma aged 18 years or older, who had received one to three previous lines of treatment from 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were randomly allocated (3:2) to treatment with either isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). In the isatuximab group, patients received intravenous isatuximab (10 mg/kg on days 1, 8, 15, and 22 of the first 28-day cycle, and days 1 and 15 of subsequent 28-day cycles). In both treatment groups, intravenous carfilzomib (20 mg/m2 on days 1 and 2 of the first cycle; and 56 mg/m2 on days 8, 9, 15, and 16 of the first cycle, and days 1, 2, 8, 9, 15, and 16 of subsequent cycles) and intravenous or oral dexamethasone (20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23) were administered. The primary endpoint of the trial was progression-free survival, which was reported previously. Treatment continued until progression, unacceptable toxicity, or patient request to discontine. The overall survival analysis reported here was planned to be conducted 3 years after the primary progression-free survival analysis in the intention-to-treat population. Additional analyses were conducted on the secondary endpoints of time to next treatment and second-progression-free survival. Reported p values are non-inferential due to hierarchical testing. This trial is registered with ClinicalTrials.gov (NCT03275285).
Between Nov 15, 2017, and March 21, 2019, 302 patients were enrolled and randomly allocated: 179 (59%) to the isatuximab group and 123 (41%) to the control group. 169 (56%) patients were male, 133 (44%) were female, 214 (71%) were White, 50 (17%) were Asian, nine (3%) were Black or African American, and three (1%) were multiracial. At data cutoff for this overall survival analysis (Feb 7, 2023), 79 (44%) overall survival events in the isatuximab group and 59 (48%) in the control group had occurred (median follow-up 56·61 months [IQR 54·90-58·02]). Median overall survival (in months) was not reached (NR; 95% CI 52·17-NR) in the isatuximab group and was 50·60 months (38·93-NR) in the control group (hazard ratio [HR] 0·855 [95% CI 0·608-1·202], nominal one-sided p=0·18). Survival probability at 48 months was 59·7% (95% CI 52·0-66·7) in the isatuximab group and 52·2% (95% CI 42·7-60·8) in the control group (based on Kaplan-Meier analysis). Improvements in time to next treatment (HR 0·583 [95% CI 0·429-0·792], nominal one-sided p=0·0002) and second-progression-free survival (0·663 [0·491-0·895], nominal one-sided p=0·0035) were observed in the isatuximab group. The most common treatment-emergent adverse events were infusion reactions (82 [46%] patients in the isatuximab group and four [3%] in the control group) and upper respiratory tract infections (71 [40%] and 34 [28%], respectively). Discontinuations due to treatment-emergent adverse events were similar between treatment groups (24 [14%] in the isatuximab group and 22 [18%] in the control group), despite an additional 30 weeks of exposure in the isatuximab group. 12 (7%) patients in the isatuximab group and six (5%) patients in the control group had a treatment-related adverse event with a fatal outcome during study treatment.
At the time of the current analysis, a difference in overall survival could not be detected between the treatment groups, and no new safety signals were observed. Collectively, the evidence suggests that isatuximab plus carfilzomib-dexamethasone is a key treatment for patients with relapsed or refractory multiple myeloma.( Yong, 2024)
2026 Update
A post hoc analysis of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-item module (EORTC QLQ-C30) and EORTC QLQ Myeloma 20-item module (EORTC QLQ-MY20) patient-reported outcome (PRO) measures from the CANDOR trial was conducted.
Median (range) duration of observation for PROs was 18.4 (0.9-50.0) months (KdD) and 10.3 (0.9-48.4) months (Kd). PRO compliance rates were high and similar between arms. Mean scores on the EORTC QLQ-C30 global health status (GHS)/quality-of-life (QOL) scale were numerically higher in the KdD than in the Kd arm and were generally sustained or trended toward improvement from baseline. Other EORTC QLQ-C30, EORTC QLQ-MY20, and EQ-5D visual analog scale (VAS) scores were generally similar between treatment arms and were stable over time, with some numerical trends favoring KdD. Risks of deterioration were similar for most scales; hazard ratios suggested improvement for KdD for EORTC QLQ-C30 social functioning, EORTC QLQ-MY20 disease symptoms, and EQ-5D VAS. Results were consistent for lenalidomide-exposed and lenalidomide-refractory subgroups. EORTC QLQ-C30 GHS/QOL scores trended toward improvement at some time points, and other scores remained generally stable when daratumumab was added to carfilzomib and dexamethasone.
These results support the benefits of KdD for the RRMM population, including lenalidomide-exposed and lenalidomide-refractory patients. (Weisel, 2025)
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Chari, A. et al.(2019) Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019 Aug 1;134(5):421-431. doi: 10.1182/blood.2019000722. Epub 2019 May 21. PMID: 31113777; PMCID: PMC6676132.
Dimopoulos MA, Moreau P, Palumbo A, et al.(2016) Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27–38 Dimopoulos MA, Stewart AK, Masszi T, Špicka I, Oriol A, Hájek R, Rosiñol L, Siegel D, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak A, San-Miguel J, Ludwig H, Palumbo A, Obreja M, Aggarwal S, Moreau P.(2017) Carfilzomib, lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study. Br J Haematol. 2017 May;177(3):404-413. doi: 10.1111/bjh.14549. Epub 2017 Feb 17. PMID: 28211560; PMCID: PMC5412871. Dimopoulos, M. et al.(2020) Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomized, multicenter, open-label, phase 3 study. Lancet Oncol. 2020; 396 (10245): P186-197. Hájek, R., Masszi, T., Petrucci, M. et al.(2016) A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia 31, 107–114 (2017). https://doi.org/10.1038/leu.2016.176 Kyprolis (carfilzomib)(2022) package insert Mang of nausea and vomiting (N/V) following first-line (1L) zolbetuximab + chemo treat in claudin-18.2 (CLDN18.2)+, HER2-, locally adv (LA) unresectable or mG/GEJ adenocarcinoma: analysis from the phase 3 SPOTLIGHT and GLOW studies. Kyprolis® (carfilzomib) [package insert]. Thousand Oaks, CA: Amgen, Inc. 2020. Martin T, Mikhael J, Hajek R, Kim K, Suzuki K, Hulin C, Garg M, Quach H, Sia H, George A, Konstantinova T, Risse ML, Asset G, Macé S, van de Velde H, Moreau P.(2022) Depth of response and response kinetics of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma. Blood Adv. 2022 Aug 9;6(15):4506-4515. doi: 10.1182/bloodadvances.2021006713. PMID: 35594559; PMCID: PMC9636327. Meid, K, et al.(2017) Long-term follow-up of a prospective clinical trial of carfilzomib, rituximab and dexamethasone in Waldenstrom’s macroglobulinemia. Blood 2017;130:2772-2772 National Comprehensive Cancer Network (NCCN).(2020) Multiple myeloma. NCCN Clinical Practice Guidelines in Oncology, Version 4.2021. Plymouth Meeting, PA: NCCN; 2020. National Comprehensive Cancer Network (NCCN).(2020) Waldenström Macroglobulinemia/ Lymphoplasmacytic Lymphoma. NCCN Clinical Practice Guidelines in Oncology, Version 1.2021. Plymouth Meeting, PA: NCCN; 2020. National Comprehensive Cancer Network (NCCN).(2024) Systemic Light Chain Amyloidosis. NCCN Clinical Practice Guidelines in Oncology, Version 2.2024. Plymouth Meeting, PA: NCCN; 2024. NCCN(2025) NCCN Drugs & Biologics Compendium for Carfilzomib (e.g., Kyprolis). National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed February 4, 2025. To view the most recent and complete version of the Compendium, go online to NCCN.org. Overall Survival Analysis from Kyprolis (carfilzomib) Phase 3 Endeavor Trial Published In The Lancet Oncology. – Press Release. https://www.amgen.com/newsroom/press-releases/2017/08/overall-survival-analysis-from-kyprolis-carfilzomib-phase-3-endeavor-trial-published-in-the-lancet-oncology Package Insert(2025) Kyprolis Thousand Oaks, CA: Amgen, Inc. 2025. Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (crd) Vs Lenalidomide and Dexamethasone (rd) in Subjects With Relapsed Multiple Myeloma - Full Text View https://www.clinicaltrials.gov/ct2/show/NCT01080391?term=01080391&draw=2&rank=1 Quach H, Nooka A, Samoylova O, Venner CP, Kim K, Facon T, Spencer A, Usmani SZ, Grosicki S, Suzuki K, Delimpasi S, Weisel K, Obreja M, Zahlten-Kumeli A, Mateos MV.(2021) Carfilzomib, dexamethasone and daratumumab in relapsed or refractory multiple myeloma: results of the phase III study CANDOR by prior lines of therapy. Br J Haematol. 2021 May 28. doi: 10.1111/bjh.17541. Rajkumar, SV.(2020) Multiple myeloma: Overview of Management. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2020. Stewart AK, Rajkumar SV, Dimopoulos MA, et al.(2015) Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–152. Stewart, AK. et al.(2018) Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. Journal of Clinical Oncology 2018 36:8, 728-734 Study Of Carfilzomib, Daratumumab and Dexamethasone For Patients With Relapsed And/or Refractory Multiple Myeloma. - Full Text View https://www.clinicaltrials.gov/ct2/show/NCT03158688?term=03158688&draw=2&rank=1 Treon S.P., et al.(2014) Carfilzomib, rituximab, and dexamethasone treatment offers a neuropathy-sparing approach for treating Waldenstrom’s macroglobulinemia. Blood 2014;124:503-510. U.S. Food and Drug Administration (FDA)(2021) Kyprolis (carfilzomib) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202714s033lbl.pdf Last accessed Feb. 08, 2022. Weisel K, Mateos MV, Landgren O, et.al.(2025) Health-Related Quality of Life in Patients With Relapsed/Refractory Multi Myeloma Treated With Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone: An Analysis of Patient-Rept Outcomes From Phase 3 CANDOR Trial. Clin Lymphoma Myeloma Leuk. 2025 Aug;25(8):590-605. doi: 10.1016/j.clml.2025.02.005. Epub 2025 Feb 19. PMID: 40087058. |
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