Medical Policy



Subject: Carfilzomib (Kyprolis®)
Document #: DRUG.00053 Current Effective Date:    06/28/2017
Status: Reviewed Last Review Date:    05/04/2017

Description/Scope

This document addresses the indications and criteria for the use of carfilzomib. Carfilzomib (Kyprolis; [Amgen® , Thousand Oaks, CA]) is a second generation selective 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.

For additional information, please refer to the following related documents:

Position Statement

Medically Necessary:

The use of carfilzomib is considered medically necessary for the treatment of multiple myeloma when the following criteria are met:

  1. There is a diagnosis of multiple myeloma; and
  2. The individual does not have New York Heart Association (NYHA) class III or IV heart failure; and
  3. The drug is being used:
    1. in combination with dexamethasone with or without lenalidomide when the individual has received one to three prior lines of therapy; or
    2. as a single agent when the individual has received one or more prior lines of therapy; or
    3. in combination with panobinostat when the individual has received at least two prior therapies, including bortezomib and an immunomodulatory agent (for example, lenalidomide or thalidomide).

The use of carfilzomib is considered medically necessary for the treatment of Waldenström's macroglobulinemia when the following criteria are met:

  1. The drug is being used as a primary agent, in combination with rituximab and dexamethasone; or
  2. The drug is being used for relapsed disease when the primary therapy of carfilzomib, rituximab, and dexamethasone was given and relapse is greater than 12 months after therapy.

Investigational and Not Medically Necessary:

The use of carfilzomib is considered investigational and not medically necessary when the above criteria are not met.

Rationale

Multiple myeloma is a malignant cancer of plasma cells that accumulates in the bone marrow. This leads to destruction of the bone and marrow failure. Normal plasma cells are found in the bone marrow and are an important part of the immune system which helps to fight infections and other diseases. Treatment for multiple myeloma can include bone marrow transplants, chemotherapy and other drugs. Multiple myeloma is sensitive to several cytotoxic drugs for both initial treatment and relapse. Many individuals will eventually relapse and there is a need for more effective therapies, particularly for those individuals who relapse after more than one therapy. The introduction of immunomodulatory drugs and the proteasome inhibitor bortezomib has led to significant improvements in survival rates in multiple myeloma. Individuals can become resistant to bortezomib and the hope is that the next generation of proteasome inhibitors will help overcome that limitation. The proteasome is a multicatalytic protease complex which is responsible for the turnover of cellular proteins. Inhibiting the proteasome leads to an increase of proteins and cell death. Tumor cells from hematologic cancers have been found to express a variant, i20S, proteasome which makes them a target for the protease inhibitor drugs.

On July 20, 2012 the United States Food and Drug Administration (FDA) granted approval for carfilzomib for the treatment of individuals with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent (lenalidomide or thalidomide), and who have demonstrated disease progression on or within 60 days of the completion of the last therapy. FDA approval was based on the response rate. Per the FDA drug label, there are no listed contraindications. However, the label does report that 7% of the participants in the qualifying trial had adverse cardiac events (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction). Individuals with NYHA Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials.

Carfilzomib is a next-generation, selective proteasome inhibitor. The FDA approval was based on an open-label, single-arm, phase II study in which participants received single-agent carfilzomib (Siegel, 2012). The primary endpoint was overall response rate. Secondary endpoints included clinical benefit response rate, duration of response, progression-free survival, and safety. Participants had at least two prior therapies including bortezomib and thalidomide and/or lenalidomide. The participants had a less than or equal to 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. A total of 266 participants were evaluated for safety and 257 were evaluated for efficacy. Ninety-five percent (95%) were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Overall response to carfilzomib was 22.9%. The median duration of response was 7.8 months. Side effects included fatigue, anemia, nausea, and thrombocytopenia.

In 2012, Vij et al reported on a phase II multicenter, open-label, single arm study in which 129 individuals with relapsed or refractory multiple myeloma who were bortezomib-naïve received 1 of 2 doses of carfilzomib. Participants were evaluated for disease response on day 15 of cycle 1, day 1 of cycles 2 through 12, and at the end of the study. The primary efficacy end point was overall response rate. Overall response rate was 47.6% in the 126 participants eligible for evaluation (3 participants were not eligible for efficacy due to missing baseline or post-baseline disease assessments). The median duration of response was 13.1 months. Side effects included fatigue, nausea, anemia, dyspnea, thrombocytopenia, and neutropenia.

A study by Berensen and colleagues (2014) reported on individuals with multiple myeloma who had been receiving bortezomib which was replaced with carfilzomib. Of the 38 participants included in the trial, 37 were treated and evaluated for efficacy and safety. This was an open-label, phase I/II trial in which bortezomib was replaced with carfilzomib in participants who had progressed while on or within 12 weeks of receiving a bortezomib-containing combination regimen. A total of 31 carfilzomib-based regimens using 14 different drug combinations were tested. One regimen of carfilzomib, ascorbic acid and cyclophosphamide reached maximum tolerated dose. The overall response rate to this regimen was 43.2% and the clinical benefit rate was 62.2%. Median progression-free survival was 8.9 months, time to progression was 9.9 months, and overall survival was 15.8 months. Adverse events included lymphopenia, thrombocytopenia, anemia, neutropenia, fever and hypokalemia.

In July 2015, the FDA approved carfilzomib in combination with lenalidomide and dexamethasone for those individuals with relapsed multiple myeloma who have received one to three prior lines of therapy. This approval was based on a 2014 study by Stewart and colleagues in whom 792 participants were randomized to one of two treatment arms; carfilzomib, lenalidomide, and dexamethasone versus the control group which received only lenalidomide and dexamethasone. Progression-free survival was the primary endpoint. Participants had relapsed multiple myeloma and had previously received one to three prior treatments. The carfilzomib group showed a median progression-free survival of 26.3 months (95% confidence interval [CI], 23.3 to 30.5) compared to the control group which showed 17.6 months (95% CI, 15.0 to 20.6). Median follow-up in the carfilzomib group was 32.3 months and 31.5 months in the control group.

The FDA revised the label in 2016 for carfilzomib to be used as a single agent when an individual has received one or more lines of therapy and as a combination agent with dexamethasone or with lenalidomide plus dexamethasone after one or more lines of therapy. In a phase III, randomized trial by Dimopoulos and colleagues (2016), the authors compared the use of carfilzomib with dexamethasone to bortezomib with dexamethasone in 929 participants with relapsed or refractory multiple myeloma. The study participants had received one to three previous treatments. With 465 participants in each treatment arm, the median progression-free survival was 18.7 months in the carfilzomib group and 9.4 months in the bortezomib group. There were 18 deaths due to adverse events in the carfilzomib group and 16 deaths in the bortezomib group. Reported adverse events included anemia, hypertension, thrombocytopenia, and pneumonia.

While carfilzomib is currently approved for relapsed or refractory multiple myeloma, clinical trials are ongoing to assess the use of carfilzomib as a first-line treatment. Jakubowiak (2012) reported on a multicenter, open-label, phase 1/2 study in which participants (n=35) received carfilzomib in combination with lenalidomide and low-dose dexamethasone induction therapy. During phase 1, the primary endpoints were the evaluation of safety and determining the maximum tolerated dose of carfilzomib. The doses of carfilzomib were escalated whereas lenalidomide and dexamethasone were given at standard low-dose induction levels. Once the maximum tolerated dose of carfilzomib was reached, additional participants were enrolled in the phase 2 expansion cohort (n=18). A total of 53 participants were enrolled in the study. In the overall population, 62% of participants achieved at least a near-complete response, 81% achieved at least a very good partial response, and 98% a partial response. The most common toxicities during induction included hyperglycemia, thrombocytopenia, anemia, edema, hypophosphatemia, and fatigue and were managed with supportive measures. Median follow-up was 13 months and 24-month progression-free survival estimate was 92%. While the results of this study are promising, the study is limited by the sample size, single-arm nonrandomized design, lack of independent central review of response results, and the study population included both transplant-eligible and –ineligible participants. Long-term follow-up is necessary with larger sample sizes.

Carfilzomib has also been given for off-label use. In 2015 the National Comprehensive Cancer Network® (NCCN) gave a 2A recommendation for the use of carfilzomib in combination with rituximab and dexamethasone as a primary therapy in Waldenström's macroglobulinemia and for relapsed disease more than 12 months following the primary therapy. In a 2014 study by Treon and colleagues, carfilzomib was given along with rituximab and dexamethasone to symptomatic individuals with Waldenström's macroglobulinemia. The primary endpoint was determination of overall response rate. In this open-label, single stage, phase 2 study, 31 participants were enrolled and received carfilzomib with dexamethasone on days 1, 2, 8, and 9, and rituximab on days 2 and 9 every 21 days. Complete response was achieved in 1 participant, very good partial response was achieved in 10 participants, partial response was achieved in 10 participants, and minimal response was achieved in 6 participants with an overall response rate of 87.1% (95% CI, 75.3-98.9%). The median follow-up was 15.4 months and 20 of the participants remained free of disease progression. The overall response rate of 87.1% in the carfilzomib, rituximab and dexamethasone regimen was found to be comparable to the bortezomib, dexamethasone and rituximab regimen which showed an overall response rate of 88-95%. The carfilzomib regimen offers an alternative with a neuropathy-sparing approach.

More recently the NCCN updated their 2A recommendation for Waldenström's macroglobulinemia for carfilzomib for disease relapse if greater than or equal to 24 months if being used as primary therapy.

Another NCCN 2A recommendation includes carfilzomib with panobinostat in individuals who have received at least two prior therapies including bortezomib and an immunomodulatory agent. In a 2015 single-arm, open-label phase I/II study by Berdeja and colleagues, 44 participants with relapsed or refractory multiple myeloma received carfilzomib in combination with panobinostat. The objective of the phase I portion of the study was to determine the maximum tolerated dose. The objective of the phase II portion was to determine efficacy of the combination with the endpoint of overall response rate. A total of 44 participants were included in the study (13 in phase I and 33 in phase II). The median number of prior therapies was five, with bortezomib making up 89% of the cases. A total of 42 participants were evaluable for phase II response. The overall response rate was 67% with 33% of participants having a very good partial response or better and 33% having a partial response. A minimum response was found in 12% of participants, 17% showed stable disease and 5% showed disease progression. When treated at the maximum planned dose, the overall response rate was 72%. For those individuals who had been previously treated with bortezomib, the overall response rate was 70%. The most common toxicities were diarrhea, nausea and vomiting, and thrombocytopenia and the combination therapy was well tolerated.

The FDA label includes several warnings including cardiac toxicities. In clinical studies, congestive heart failure, pulmonary edema, or decreased ejection fraction (either a new onset or a worsening of previous condition) has led to death due to cardiac arrest within 1 day of administration of carfilzomib. Individuals with New York Heart Association Class III and IV heart failure were ineligible for clinical trials.

Background/Overview

Multiple myeloma is a systemic malignancy of plasma cells that accumulate in the bone marrow, leading to destruction of bone and failure of the bone marrow. Multiple myeloma is highly treatable but rarely curable. However, when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma it is potentially curable. Multiple myeloma accounts for approximately 10% of all hematologic cancers. The American Cancer Society has estimated 30,280 new cases of multiple myeloma will be diagnosed in the United States in 2017, with an estimated 12,790 deaths. The stage of the disease at presentation is a strong determinant of survival, but has little influence on the choice of therapy since almost all individuals (except for those with solitary bone tumors or extramedullary plasmacytomas) have generalized disease. Multiple myeloma affects mostly older individuals around 62 years of age. The age and general health of the individual, prior therapy and the presence of complications of the disease influence treatment selection. The median survival in the prechemotherapy era was about 7 months. Multiple myeloma has demonstrated chemosensitivity to initial treatment or treatment for relapsed disease. Improvements in newer treatments have resulted in an increase in 5-year survival which is currently around 40%.

Waldenström's macroglobulinemia is a type of non-Hodgkin's lymphoma (also called lymphoplasmacytic lymphoma). It is a rare condition with an incidence rate of about three cases per million people per year in the United States. Approximately 1000 to 1500 people are diagnosed with Waldenström's macroglobulinemia each year. The cancer cells make large amounts of an abnormal protein called a macroglobulin. It starts in the B lymphocytes and grows mostly in the bone marrow where the abnormal cells crowd out the normal cells. This can lead to anemia and low numbers of white cells which can make it hard to fight off infection.

Definitions

Multiple myeloma: A type of cancer that begins in plasma cells (white blood cells that produce antibodies).

Refractory disease: Illness or disease that does not respond to treatment.

Relapse: After a period of improvement, the return of signs and symptoms of cancer.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS    
J9047 Injection, carfilzomib, 1 mg [Kyprolis]  
   
ICD-10 Diagnosis  
C83.00-C83.09 Small cell B-cell lymphoma [lymphoplasmacytic lymphoma]
C88.0 Waldenström's macroglobulinemia
C90.00-C90.32 Multiple myeloma and malignant plasma cell neoplasms
Z85.79 Personal history of other malignant neoplasms of lymphoid, hematopoietic and related tissues

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Berdeja JG, Hart LL, Mace JR, et al. Phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Haematologica. 2015; 100(5):670-676.
  2. Berenson JR, Hilger JD, Yellin O, et al. Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy. Leukemia. 2014; 28(7):1529-1536.
  3. Dimopoulos MA, Moreau P, Palumbo A, et al. 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.
  4. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012; 120(9):1801-1809.
  5. Khan ML, Stewart AK. Carfilzomib: a novel second-generation proteasome inhibitor. Future Oncol. 2011; 7(5):607-612.
  6. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013; 98(11):1753-1761.
  7. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012; 120(14):2817-2825.
  8. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015; 372(2):142-152.
  9. Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia. Blood. 2014; 124(4):503-510.
  10. Vij R, Wang M, Kaufman JL, et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012; 119(24):5661-5670.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Carfilzomib (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated periodically. Available at: http://www.micromedexsolutions.com. Accessed on April 11, 2017.
  2. Kyprolis (carfilzomib) [Product Information]. South San Francisco, CA. Onyx Pharmaceuticals. November 17, 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202714s015lbl.pdf . Accessed on April 8, 2017.
  3. National Cancer Institute. Common terminology criteria for adverse events. Version 4.03. June 2010. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed on April 8, 2017.
  4. National Comprehensive Cancer Network® . NCCN Drugs & Biologic Compendium (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on April 8, 2017.
  5. NCCN Clinical Practice Guidelines in Oncology. © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on April 8, 2017.
    • Multiple Myeloma (V.3.2017). Revised November 28, 2016.
    • Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma (V.1.2017). Revised January 31, 2017.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org/. Accessed on April 8, 2017.
  2. National Cancer Institute. Available at: www.cancer.gov. Accessed on April 8, 2017.
Index

Carfilzomib
Kyprolis
Multiple myeloma
Waldenström's Macroglobulinemia 

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Reviewed 05/03/2017 Hematology/Oncology Subcommittee review. Updated formatting in Position Statement section. Updated Rationale, Coding, Background/Overview and References sections.
Revised 05/05/2016 MPTAC review.
Revised 05/04/2016 Hematology/Oncology Subcommittee review. Revised medically necessary criteria for multiple myeloma. Updated Rationale and Reference sections.
Revised 11/05/2015 MPTAC review.
Revised 11/04/2015 Hematology/Oncology Subcommittee review. Added medically necessary indication for one to three prior lines of therapy. Added medically necessary indications for Waldenström's macroglobulinemia. Updated Rationale, Background/Overview, Coding, References, and Index sections. Removed ICD-9 codes from Coding section.
Reviewed 11/13/2014 MPTAC review.
Reviewed 11/12/2014 Hematology/Oncology Subcommittee review. Updated Rationale, Background/Overview, and References.
Reviewed 11/14/2013 MPTAC review.
Reviewed 11/13/2013 Hematology/Oncology Subcommittee review. Updated Rationale, Background/Overview and References.  Updated Coding section with 01/01/2014 HCPCS changes; removed C9295 deleted 12/31/2013.
New 11/08/2012 MPTAC review.
New 11/07/2012 Hematology/Oncology Subcommittee review. Initial document development.