Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Daratumumab (Darzalex™)

Policy #:08.01.29d

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

MEDICALLY NECESSARY

Daratumumab (Darzalex™) is considered medically necessary and, therefore, covered for individuals who have been newly diagnosed with multiple myeloma, when given in combination with bortezomib, melphalan, and prednisone, and who are ineligible for autologous stem cell transplant.

Daratumumab (Darzalex™) monotherapy is considered medically necessary and, therefore, covered for the treatment of relapsed, progressive, or refractory multiple myeloma when either of the following criteria have been met:
  • The individual has previously received at least three prior lines of therapy, including a proteasome inhibitor (PI)1 AND an immunomodulatory agent2
  • The individual is double-refractory to a PI1 AND an immunomodulatory agent2 (i.e., disease progression on or within 60 days of the last dose of each agent)

Daratumumab (Darzalex™) is considered medically necessary and, therefore, covered for the treatment of relapsed, progressive, or refractory multiple myeloma in individuals who have received one of the following regimens:
  • At least one prior therapy and daratumumab (Darzalex™) is used in combination with either:
    • Lenalidomide (Revlimid®) and dexamethasone
    • Bortezomib (Velcade®) and dexamethasone
  • At least two prior therapies including lenalidomide and a proteasome inhibitor1, and daratumumab (Darzalex™) is used in combination with pomalidomide (Pomalyst®) and dexamethasone

1Examples of proteasome inhibitors (PI) include bortezomib (Velcade®) and carfilzomib (Kyprolis™)

2Examples of immunomodulary agents include lenalidomide (Revlimid®), pomalidomide (Pomalyst®), and thalidomide (Thalomid®)

EXPERIMENTAL/INVESTIGATIONAL

All other uses for daratumumab (Darzalex™) are considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.
Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, daratumumab (Darzalex) is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Daratumumab (Darzalex) was approved by the FDA on November 16, 2015 for the treatment of individuals with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent. Supplemental approvals for daratumumab (Darzalex™) have since been issued by the FDA. Daratumumab (Darzalex™) is administered as an intravenous infusion.

PEDIATRIC USE

The safety and effectiveness of daratumumab (Darzalex) in pediatric individuals have not been established.

Description

Like many types of malignancies, further treatment of multiple myeloma after relapsed, progressive, or refractory disease usually yields a shorter duration and lower quality of response compared to the initial response. There is a high demand for agents that treat multiple myeloma that does not respond or that progresses after first- or subsequent-line therapy.

On November 16, 2015, the US Food and Drug Administration (FDA) granted approval of daratumumab (Darzalex™), an intravenous monoclonal antibody, for the treatment of individuals with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.

CD38 is a glycoprotein expressed on the surface of hematopoietic cells (including lymphoid and myeloid cells). When multiple myeloma is present, there is an overexpression of CD38 on malignant plasma cells. Daratumumab (Darzalex™) works by binding to CD38 and inhibiting the growth of the malignant tumor cells through multiple mechanisms, including complement-dependent cytotoxicity (CDC) (causing tumor cell lysis and death), antibody-dependent cell-mediated cytotoxicity (ADCC) (causing tumor cell death by non-phagocytic processes via the activation of natural killer cells, macrophages, etc.), and antibody-dependent cellular phagocytosis (ADCP) by macrophages.

PEER-REVIEWED LITERATURE

SUMMARY
Newly Diagnosed Multiple Myeloma: In Combination with Bortezomib, Melphalan, and Prednisone (VMP) in Individuals Ineligible for Autologous Stem Cell Transplant

The approval for daratumumab (Darzalex™) in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed multiple myeloma was based on an open-label, randomized, active-controlled, Phase 3 study of 706 individuals (ALCYONE study). Individuals were randomized to treatment with either daratumumab (Darzalex™) in combination with VMP (D-VMP group) or to treatment with VMP alone. The study showed an improvement in progression-free survival (PFS) in the D-VMP arm as compared to the VMP arm; the median PFS had not been reached in the D-VMP arm and was 18.1 months in the VMP arm (p<0.0001), representing 50% reduction in the risk of disease progression or death in individuals treated with D-VMP.

Monotherapy for Multiple Myeloma After Three Prior Lines of Therapy

The approval of daratumumab (Darzalex™) was based on the results of a two-part, open-label, multicenter, Phase 2 study. Enrolled in the trial were individuals who had responded to at least one previous treatment regimen, received an alkylating agent alone or in combination with other myeloma treatments, received at least three previous lines of treatment that included a proteasome inhibitor and an immunomodulatory drug, or had disease double-refractory to the most recent proteasome inhibitor and immunomodulatory drug they had received. (Refractory disease was defined as disease progression on or within 60 days of the last dose). All individuals had an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or lower.

Part 1 was a dose-defining study of 34 individuals randomized (1:1) to either daratumumab (Darzalex™) 8 mg/kg every four weeks or 16 mg/kg weekly for eight weeks, then 16 mg/kg every two weeks for 16 weeks, then 16 mg/kg every four weeks. A first interim analysis was performed about eight weeks after the last individual's enrollment; at that time, the individual could crossover to the more effective dose if appropriate. A second interim analysis was conducted after another 25 individuals were treated for at least 8 weeks.

Part 2 was an expansion cohort of 65 individuals which brought the total number of individuals in the study to 106. All individuals were administered the optimal dose of 16 mg/kg weekly for eight weeks, then 16 mg/kg every two weeks for 16 weeks, then 16 mg/kg every four weeks thereafter.

The primary efficacy endpoint was overall response rate (ORR), which is a measurement of a positive response to treatment. In this study the ORR was the sum of partial response, very good partial response, complete response, and stringent complete response. The results concluded that the ORR was 29.2%, and there was a median duration of response of 7.4 months.

In Combination with Lenalidomide (Revlimid®) or Bortezomib (Velcade®) and Dexamethasone for Multiple Myeloma After at Least One Prior Line of Therapy

The approval of daratumumab (Darzalex™) in combination with lenalidomide (Revlimid®) and dexamethasone for the treatment of multiple myeloma after one prior therapy was based on a phase 3, randomized, open-label trial in 569 individuals. These individuals had relapsed or refractory multiple myeloma and received one or more previous lines of therapy. They were assigned to receive either daratumumab, lenalidomide and dexamethasone (daratumumab group, n=286), or lenalidomide and dexamethasone (control group, n=283). The primary endpoint of this study was progression-free survival. At a median follow-up of 13.5 months, there was a total of 169 events of disease progression or death; 53 (18.5%) in daratumumab group and 116 (41%) in the control group. The median progression-free survival was not reached in the daratumumab group, as compared to 18.4 months in the control group; however, the rate of progression-free survival at 12 months was 85.7% in the daratumumab group versus 63.2% in the control group. In conclusion, the group treated with daratumumab experienced a significant progression-free survival and higher rates of overall response in individuals with relapsed or refractory multiple myeloma. The daratumumab group did have higher rates of adverse reactions (including neutropenia and infusion-related reactions), but this did not result in increased treatment discontinuation or death.

The use of daratumumab (Darzalex™) in combination with bortezomib (Velcade®) and dexamethasone for multiple myeloma was approved based on a phase 3, open-label, randomized, multicenter trial. 498 individuals with relapsed or refractory multiple myeloma were randomly assigned bortezomib and dexamethasone (control group) or daratumumab, bortezomib, and dexamethasone (dartumumab group). The primary endpoint was progression-free survival, which was defined as the time from the date of randomization to date of disease progression or death. At a median follow-up period of 7.4 months, a total of 189 events of disease progression or death had occurred; 67 in daratumumab group and 122 in the control group. The 12-month progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. The overall response rate, which was a secondary endpoint of the study, was 82.9% in the daratumumab group and 63.2% in the control group. In conclusion, this study determined that, for individuals with relapsed or refractory multiple myeloma, the combination of daratumumab, bortezomib, and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone. Additionally, the daratumumab group did experience infusion-related reactions (i.e., dyspnea, bronchospasm, and cough) and higher rates of thrombocytopenia and neutropenia.

In Combination with Pomalidomide (Pomalyst®) and Dexamethasone for Multiple Myeloma After Two Prior Therapies Including Lenalidomide and a Proteasome Inhibitor

Approval for daratumumab (Darzalex™) in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma was based on an open-label trial including 103 individuals. The overall response rate (ORR) was 60% with a median progression-free survival (PFS) of 8.8 months, 12 month PFS of 42%, and median time to progression of 10.4 months.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References


American Hospital Formulary Service (AHFS). Drug Information 2018. Darzalex. [Lexicomp Online Web site] 02/07/2018. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed August 16, 2018.

Daratumumab (Darzalex). [Prescribing information]. Janssen Biotech, Inc., Horsham, PA 19044.; 06/2018. Available at: https://www.darzalex.com/. Accessed August 14, 2018.

Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.

Elsevier’s Gold Standard Clinical Pharmacology Compendium. Daratumumab (Darzalex). 05/09/2018. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/monograph/4729?sec=monindi&n=DARZALEX [via subscription only]. Accessed August 16, 2018.

Jelinek T, Hajek R. Monoclonal antibodies - A new era in the treatment of multiple myeloma. Blood Rev. 2015 Aug 24. pii: S0268-960X(15)00065-X. [Epub ahead of print].

Lexi-Drugs Compendium. daratumumab (Darzalex). 07/26/2018. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5928764 [via subscription only]. Accessed August 16, 2018.

Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Jan 6. pii: S0140-6736(15)01120-4. [Epub ahead of print].

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Multiple Myeloma (version 01.2019). 08/02/2018. [NCCN Web site]. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#myeloma [via free subscription]. Accessed August 16, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. Daratumumab (Darzalex). [NCCN Web site]. 2018. Available at: http://www.nccn.org/professionals/drug_compendium/content/contents.asp [via subscription only]. Accessed August 16, 2018.

Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.

Rajkumar SV. Treatment of relapsed or refractory multiple myeloma. July 30, 2018. [UpToDate WebSite]. Available at: http://www.uptodate.com/contents/treatment-of-relapsed-or-refractory-multiple-myeloma?source=search_result&search=daratumumab&selectedTitle=4%7E10. Accessed August 16, 2018.

Truven Health Analytics. Micromedex® DrugDex® Compendium. daratumumab (Darzalex). June 26, 2018. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed August 16, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. daratumumab (Darzalex) drug label [FDA Web site]. 06/2018. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed August 16, 2018.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

C90.00 Multiple myeloma not having achieved remission

C90.01 Multiple myeloma in remission

C90.02 Multiple myeloma in relapse



HCPCS Level II Code Number(s)

J9145 Injection, daratumumab, 10 mg


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References


Policy History

Revisions from 08.01.29d
11/05/2018This version of the policy will become effective 11/05/2018.

This policy has been updated to reflect new FDA-approved regimens for newly diagnosed multiple myeloma.


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 11/05/2018
Version Issued Date: 11/05/2018
Version Reissued Date: N/A

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