Archived Policies - Prescription Drugs


Kyprolis (carfilzomib)

Number:RX502.040

Effective Date:03-01-2016

End Date:06-30-2016

Coverage:

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, Hayes, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Kyprolis (carfilzomib) may be considered medically necessary for the following:

In combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma (MM) who have received at least one prior therapy; or

As a single agent for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy; or

As a treatment for Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma.

Kyprolis (carfilzomib is considered experimental, investigational and/or unproven for all other indications.

Description:

Kyprolis™ (carfilzomib) targets and inhibits the proteasome enzyme complex within the cell. The proteasome (a multi-catalytic protease present in all eukaryotic cells), is part of the cellular machinery and has many functions. The proteasome plays an important role in the regulation of cell cycle, neoplastic growth, and metastasis. In the laboratory, it has been shown that cancer cells are more susceptible to the effects of proteasome inhibitors, than normal cells are. Proteasome inhibitors (PIs) specifically induce apoptosis (cell suicide) in cancer cells.

Carfilzomib was approved by the U. S. Food, Drug Administration (FDA) in 2012 for patients with multiple myeloma (MM) who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. Carfilzomib was also FDA approved in July 2015 for use in combination with lenalidomide and dexamethasone (KRd) for the treatment of patients with relapsed MM who have received one to three prior lines of therapy.

Rationale:

In Combination with Lenalidomide and Dexamethasone for the treatment of Patients with Relapsed Multiple Myeloma (MM)

The t approval was based on a randomized, open-label, multicenter study which evaluated the combination of Kyprolis with lenalidomide and low-dose dexamethasone (KRd) versus lenalidomide and low-dose dexamethasone alone (Rd) in patients with relapsed multiple myeloma who had received 1 to 3 prior lines of therapy. (A line of therapy is a planned course of treatment [including sequential induction, transplantation, consolidation and/or maintenance] without an interruption for lack of efficacy, such as for relapse or progressive disease.) Patients who had the following were excluded from the trial: refractory to bortezomib in the most recent regimen, refractory to lenalidomide and dexamethasone in the most recent regimen, creatinine clearance rates < 50 mL/min, New York Heart Association Class III to IV congestive heart failure, or myocardial infarction within the last 4 months. Kyprolis treatment 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 792 patients in this study were randomized 1:1 to the KRd or Rd arm. The demographics and baseline characteristics were well-balanced between the two arms. Only 53% of the patients had testing for genetic mutations; a high-risk genetic mutation was identified for 12% of patients in the KRd arm and in 13% in the Rd arm.

Patients in the KRd arm demonstrated improved progression-free survival (PFS) compared with those in the Rd arm (HR = 0.69, with 2-sided p-value = 0.0001) as determined using standard objective 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 (95% CI: 23.3 to 30.5 months) in the KRd arm vs. 17.6 months (95% CI: 15.0 to 20.6 months) in the Rd arm. The results of overall survival (OS) were not significantly different at the interim analysis.

The median duration of response was 28.6 months (95% CI: 24.9 to 31.3 months) for the 345 patients achieving a response in the KRd arm and 21.2 months (95% CI: 16.7 to 25.8 months) 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.

Monotherapy for Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Study 2 was a single-arm, multicenter clinical trial of Kyprolis monotherapy. Eligible patients were those with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and had 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. Patients were excluded from the trial if they were refractory to all prior therapies, or with total bilirubin levels ≥ 2 × upper limit of normal (ULN); creatinine clearance rates < 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; or pleural effusion.

Kyprolis was administered intravenously over 2 to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20 mg/m2 at each dose in Cycle 1, and 27 mg/m2 in subsequent cycles. Dexamethasone 4 mg orally or intravenously was administered prior to Kyprolis doses in the first and second cycles. A total of 266 patients were enrolled. The median number of cycles started was four.

The primary endpoint was the overall response rate (ORR) as determined by Independent Review Committee assessment using International Myeloma Working Group criteria. The ORR (stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]) was 22.9% (95% CI: 18.0, 28.5) (N = 266) (see Table 12). The median duration of response (DOR) was 7.8 months (95% CI: 5.6, 9.2).

Waldenstrom’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma

Carfilzomib, rituximab, and dexamethasone produced an overall response rate of 87.1% and a major response rate (partial response or better) of 67.7% in a single-arm study (N=31) of symptomatic patients with Waldenstrom macroglobulinemia who were naive to bortezomib and rituximab, and had received no more than 1 prior therapy. At a median follow-up period of 15.4 months, the median time to progression had not been reached. Median time to best response was more than 12.8 months. Median IgM levels decreased from 3375 mg/dL at baseline to 749 mg/dL at best response; median bone marrow involvement decreased from 60% to 5%; and median HCT increased from 32.3% to 41.3%. MYD88 (L265P) mutation was detected in 96.6% of the 30 patients with results, and the 1 patient with wild-type MYD88 achieved a very good partial response. Response rate was not significantly different in the 36.7% of patients with CXCR4 (WHIM) compared with CXCR wild-type (90.9% vs 85%). Grade 2 or higher toxicity included peripheral neuropathy (3.2%), dexamethasone-related hyperglycemia (77.4%), carfilzomib-related hyperlipasemia (41.9%), and rituximab-related infusion reactions (19.4%).

In 2014 Treon, et al. (2) noted that carfilzomib, rituximab and dexamethasone (CaRD) offers a neuropathy sparing approach for proteasome inhibitor based therapy for Waldenström’s macroglobulinemia. In this study carfilzomib, rituximab, and dexamethasone (CaRD) were examined in symptomatic WM patients’ naïve to bortezomib and rituximab. Protocol therapy consisted of intravenous carfilzomib, 20 mg/m2 (cycle 1) and 36 mg/m (2) (cycles 2-6), with intravenous dexamethasone, 20 mg, on days 1, 2, 8, and 9, and rituximab, 375 mg/m (2), on days 2 and 9 every 21 days. Maintenance therapy followed 8 weeks later with intravenous carfilzomib, 36 mg/m (2), and intravenous dexamethasone, 20 mg, on days 1 and 2, and rituximab, 375 mg/m(2), on day 2 every 8 weeks for 8 cycles. Overall response rate was 87.1% (1 complete response, 10 very good partial responses, 10 partial responses, and 6 minimal responses) and was not impacted by MYD88 (L265P) or CXCR4 (WHIM) mutation status. With a median follow-up of 15.4 months, 20 patients remain progression free. Grade ≥2 toxicities included asymptomatic hyperlipasemia (41.9%), reversible neutropenia (12.9%), and cardiomyopathy in 1 patient (3.2%) with multiple risk factors, and PN in 1 patient (3.2%) which was grade 2. Declines in serum IgA and IgG were common. This trial is registered at www.clinicaltrials.gov as #NCT01470196.

The National Comprehensive Cancer Network (NCCN, version 2.2016) recommends carfilzomib as a component of CaRD (carfilzomib, rituximab, and dexamethasone) regimen in Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma as primary therapy. (3)

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J9047

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. FDA – Department of Health and Human Services. Kyprolis® (carfilzomib) Label. <http://www.fda.gov> Accessed September 2015.

2. 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.

3. NCCN Guidelines – Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma Guidelines. – Version 2.2016. National Comprehensive Cancer Network. Available at <http://www.nccn.org> (Accessed September 2015).

4. NCCN – Multiple Myeloma Guidelines – Version 2.2016. National Comprehensive Cancer Network. Available at <http://www.nccn.org> (Accessed September 2015).

5. Truven Health Analytics Inc — Kyprolis® (carfilzomib). Micromedex Subscriptions. Available at <Micromedex.com> (Accessed September 2015).

Policy History:

Date Reason
3/1/2016 New medical document. Kyprolis (carfilzomib) may be considered medically necessary for the following: 1) In combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received at least one prior therapy, 2) As a single agent for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy and 3) As a treatment for Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma. Kyprolis is considered experimental, investigational and/or unproven for all other indications.

Archived Document(s):

Title:Effective Date:End Date:
Kyprolis (carfilzomib)08-15-201706-14-2018
Kyprolis (carfilzomib)07-01-201608-14-2017
Kyprolis (carfilzomib)03-01-201606-30-2016
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