Description
Daratumumab (Darzalex) is an immunoglobulin G1 kappa (IgG1k) human monoclonal antibody against CD38 antigen, produced in a mammalian cell line using recombinant DNA technology.

CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity.

Daratumumab (Darzalex) is the first monoclonal antibody approved for treating multiple myeloma.

Multiple myeloma is a form of blood cancer that occurs in infection-fighting plasma cells (a type of white blood cell) found in the bone marrow. These cancerous cells multiply, produce an abnormal protein and push out other healthy blood cells from the bone marrow. The disease may result in a weakened immune system and cause other bone or kidney problems.

Policy
DARZALEX/DARZALEX FasPRO is a CD38-directed cytolytic antibody is considered MEDICALLY NECESSARY:

Multiple myeloma (newly diagnosed):

• Treatment of newly diagnosed multiple myeloma (in combination with bortezomib, thalidomide, and dexamethasone) in adults who are eligible for autologous stem cell transplant
• Treatment of newly diagnosed multiple myeloma (in combination with bortezomib, melphalan, and prednisone) in adults who are ineligible for autologous stem cell transplant
• Treatment of newly diagnosed multiple myeloma (in combination with lenalidomide and dexamethasone) in adults who are ineligible for autologous stem cell transplant

Multiple myeloma (relapsed/refractory):

• Treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone and lenalidomide) in adults who have received at least 1 prior therapy
• Treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone and bortezomib) in adults who have received at least 1 prior therapy
• Treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone and carfilzomib) in patients who have received 1 to 3 prior therapies
• Treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone and pomalidomide) in adults who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor
• Treatment of relapsed or refractory multiple myeloma (as monotherapy) in adults who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent

Light Chain Amyloidosis

• Treatment of systemic light chain amyloidosis when the member has relapsed or refractory disease
• DARZALEX FasPRO as medically necessary for newly diagnosed members when used in combination with bortezomib, cyclophosphamide and dexamethasone; or for relapsed or refractory disease

T- Acute Lymphoblastic Leukemia

• Treatment of relapsed/refractory CD38 antigen directed single agent therapy for relapsed/refractory T- Acute Lymphoblastic Leukemia

Continuation of Therapy

Continuation of daratumumab (Darzalex) or daratumumab and hyaluronidase-fihj (Darzalex Faspro) therapy medically necessary for when initial criteria has been met and member show clinical response to therapy.

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be MEDICALLY NECESSARY if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and NOT MEDICALLY NECESSARY.

Policy Guidelines
Pre-medicate with corticosteroids, antipyretics and antihistamines.

Dilute and administer as an intravenous infusion.
Recommended dose is 16 mg/kg actual body weight according to the following schedule.

Monotherapy and in combination with lenalidomide and low-dose dexamethasone:

Weeks 1 to 8                                                                             weekly (total of 8 doses)
Weeks 9 to 24                                                                           every two weeks (total of 8 doses)
Week 25 onward until disease progression                              every four weeks

In combination with bortezomib and dexamethasone:

Weeks 1 to 9                                                                            weekly (total of 9 doses)
Weeks 10 to 24                                                                        every three weeks (total of 5 doses)
Week 25 onward until disease progression                             every four weeks              

Administer post-infusion medications.

References 

1. Darzalex (daratumumab) injection package insert. Horsham, PA: Janssen Biotech, Inc. November 2016.
2. U.S. Food and Drug Administration (FDA). FDA approves Darzalex for patients with previously treated multiple myeloma. Press Announcements. Silver Spring, MD: FDA; November 16, 2015. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm472875.htm. Accessed December 14, 2016.
3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. Available at: www.clinicalpharmacilogy-ip.com. Accessed 5/25/17.
4. Dimopoulos MA, Oriol A, Nahi H, et al.; POLLUX Investigators. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. 
5. FDA Orphan Drug Designations and Approvals [Internet]. Washington, D.C. [cited 2017 May 30]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/.
6. Lokhorst HM, Plesner T, and Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 2015;373(13):1207-1219.
7. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 05/25/17.
8. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 05/25/17.
9. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 3.2017 Multiple Myeloma. Available at http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. Accessed 05/30/17.
10. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66.

Coding Section 

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.

Definitions 

1. Heavy chain — the larger component of an immunoglobulin. There are five types: IgG, IgA, IgM, IgD, and IgE.
2. Immunoglobulins (aka antibodies) — proteins made by normal plasma cells that have an important role in fighting infection as part of the humoral immune response. Antibodies are composed of two heavy chains and two light chains that form a larger complex. Each plasma cell produces only one type of heavy chain and one type of light chain.
3. Light chain — the smaller component of an immunoglobulin. There are two types: kappa and lambda.
4. Minimal response (MR) (according to the Revised Uniform Response Criteria by the International Myeloma Working Group) — ALL of the following:
   •  ≥ 25% but ≤ 49% reduction of serum M-protein
   • Reduction in 24-hour urine M-protein by 50% to 89%
   • In addition, if present at baseline, 25% to 49% reduction in size of soft tissue plasmacytomas is also required
   • No increase in size or number of lytic bone lesions (development of compression fractures dose not exclude response).
5. Myeloma protein (M-protein) — a nonfunctional immunoglobulin protein or protein fragment produced by malignant plasma cells (or myeloma cells). Since myeloma cells are monoclonal, the M-proteins for a given patient are structurally identical. Both portions of an immunoglobulin (the heavy chain and light chain) can be found in the serum, while only light chains can be found in the urine.
6. Plasma cell — a fully differentiated B lymphocyte (a type of white blood cell) that is specialized for immunoglobulin production and is found primarily in bone marrow.
7. Primary refractory MM — patients who never achieve at least a MR to initial induction therapy and progress while on therapy
8. Progressive MM — at least a 25% increase from nadir in the serum M-protein (absolute increase must be ≥ 0.5 g/dL) or urine M-protein (absolute increase must be ≥ 200 mg/24 hours), or in the difference between involved and uninvolved serum-free light-chain (FLC) levels (with an abnormal FLC ratio and FLC difference > 100 mg/L).
9. Relapsed and refractory MM — patients who never achieve at least a MR or who progress within 60 days of their last therapy.
10. Serum-free light chain assay (SFLCA) — a test that detects the amount of unbound or free light chains (i.e., not attached to a heavy chain) in the serum. Normal values - kappa: 3.3 to 19.4 mg/L, lambda: 5.71 to 26.3 mg/L, kappa/lambda ratio: 0.26 – 1.65 (0.37 – 3.1 if renal impairment).
11. Serum protein electrophoresis (SPEP) — a test that detects and quantifies the amount of M-protein in the serum. An serum M-protein of greater than 30 g/L is consistent with a diagnosis of MM.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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