Coverage Policies

Effective Date:

a)    This policy will apply to all services performed on or after the above revision date which will become the new effective date.

b)    For all services referred to in this policy that were performed before the revision date, contact customer service for the rules that would apply.

1)    Darzalex (Daratumumab) and Darzalex Faspro require prior authorization.

2)    Darzalex is used to treat multiple myeloma.

3)    Darzalex is a specialty medication covered under the medical benefit.

Darzalex (Daratumumab) or Darzalex Faspro is considered medically necessary for patients meeting the following criteria:

A. Multiple Myeloma (must meet all):

1)    Diagnosis of MM;

2)    Prescribed by or in consultation with an oncologist or hematologist;

3)    Age ≥ 18 years;

4)    Darzalex or Darzalex Faspro is prescribed in one of the following ways (a or b):

a.    Primary therapy (i or ii):

                                          i.    Ineligible for ASCT (1 or 2):

1.    In combination with lenalidomide* and dexamethasone;

2.    In combination with bortezomib*, melphalan, and prednisone;

                                        ii.    Eligible for ASCT in combination with one of the following:

1.    bortezomib*, thalidomide*, and dexamethasone;

2.    bortezomib*, lenalidomide*, and dexamethasone;

3.    bortezomib*, cyclophosphamide, dexamethasone;

4.    carilzomib*, lenalidomide*, and dexamethasone;

b.    Subsequent therapy (I, ii, or iii):

                                          i.    In combination with dexamethasone and either lenalidomide*, bortezomib* (with or without cyclophosphamide), carfilzomib*, or Xpovio* after ≥ 1 prior

                                        ii.    In combination with pomalidomide* and dexamethasone after ≥ 1 prior therapies, including both of the following:

1.    An immunomodulatory agent (e.g., thalidomide*, lenalidomide*);

2.    A PI (e.g., ixazomib*, bortezomib*, carfilzomib*);

iii. As monotherapy after > 3 prior lines of therapy including a PI and an immunomodulatory agent or who are double-refractory to a PA and an immunomodulatory agent;

5)    Request meets one of the following (a or b):*

a.    Dose does not exceed the FDA dosing limits.

b.    Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).

B. Systemic Light Chain Amyloidosis (must meet all):

1)    Diagnosis of systemic light chain amyloidosis;

2)    Prescribed by or in consultation with an oncologist or hematologist;

3)    Age ≥ 18 years;

4)    Member meets one of the following (a or b):

a.    Darzalex Faspro is prescribed in combination with bortezomib*, cyclophosphamide, and dexamethasone;

b.    Darzalex or Darzalex Faspro is prescribed for relapsed or refractory disease after ≥ 1 prior therapy (e.g., bortezomib*, lenalidomide*) (off-label**);

5)    Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).*

Continued Therapy

All Indications above (must meet all):

1. Currently receiving medication via QualChoice benefit, or documentation supports that member is currently receiving Darzalex of Darzalex Faspro for a covered indication and has received this medication for at least 30 days;

2. Member is responding positively to therapy;

3. If request is for a dose increase, request meets one of the following (a or b):*

a. New dose does not exceed the maximum indicated;

b. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).

*Prescribed regimen must be FDA-approved or recommended by NCCN.

Approval duration: 12 months

Multiple Myeloma:

Schmidt-Wolf et al (2014) reviewed the development in the treatment of relapsed/refractory multiple myeloma (MM) during the past 10 years.  The present standard-of-care in progressive or refractory MM was elaborated by the Working Group "Refractory Multiple Myeloma" using an extensive literature search for studies published between 2003 and 2013.  Outside of clinical trials, high-dose chemo-therapy (HDCT) with stem cell transplantation (SCT) is recommended in physically fit patients (up to 75 years of age) without significant co-morbidities.  Ongoing studies address the question regarding the least toxic and the most effective treatment; thus, inclusion of patients in therapeutic trials and use of novel agent combinations is highly recommended (e.g., with 3rd generation immunomodulatory drugs [Pomalidomide], new proteasome inhibitors [PIs] such as Carfilzomib, Ixazomib or Oprozomib, antibodies, such as Elotuzumab, Daratumumab or SAR650984, Siltuximab, Tabalumab, Denosumab, Romosozumab, Bruton`s tyrosine kinase [BTK]-, heat shock protein [HSP]-inhibitors and other innovative agents).

El-Amm and Tabbara (2015) stated that the treatment of MM has evolved significantly over the past 2 decades as a consequence of the use of HDCT and autologous SCT, and the subsequent introduction of the immunomodulatory agents (thalidomide and Lenalidomide) and the PI (Bortezomib).  The median overall survival (OS) of MM patients has increased significantly with patients younger than 50 years of age experiencing a 10-year survival rate of approximately 40 %.  However, despite the increased effectiveness of the 1st-line agents, the majority of patients will eventually relapse and become drug-resistant.  Promising novel therapies have recently emerged and are being used to treat relapsed and refractory patients.  These researchers examined the clinical data regarding these emerging therapies that include new generation of PIs (e.g., Carfilzomib, Ixazomib, Oprozomib, and Marizomib), immunomodulatory drugs (Pomalidomide), monoclonal antibodies (mAbs) (Elotuzumab and Daratumumab), signal transduction modulator (Perifosine), and histone deacetylase inhibitors (Vorinostat and Panobinostat).

Daratumumab is an IgG1κ human mAb that binds to cluster of differentiation 38 (CD38; also known as cyclic ADP ribose hydrolase) and inhibits the growth of CD38-expressing tumor cells by inducing apoptosis directly through Fc-mediated cross-linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity, antibody dependent cell mediated cytotoxicity, and antibody dependent cellular phagocytosis.  Myeloid derived suppressor cells and a subset of regulatory T cells (CD38+Tregs) express CD38 and are susceptible to Daratumumab-mediated cell lysis.

In a phase I/II clinical trial, Lokhorst et al (2015) examined the safety and effectiveness of Daratumumab in patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy.  In part 1, the dose-escalation phase, these researchers administered Daratumumab at doses of 0.005 to 24 mg/kg body weight.  In part 2, the dose-expansion phase, 30 patients received 8 mg/kg of Daratumumab and 42 received 16 mg/kg, administered once-weekly (8 doses), twice-monthly (8 doses), and monthly for up to 24 months.  End-points included safety, effectiveness, and pharmacokinetics.  No maximum tolerated dose (MTD) was identified in part 1; in part 2, the median time since diagnosis was 5.7 years.  Patients had received a median of 4 prior treatments; 79 % of the patients had disease that was refractory to the last therapy received (64 % had disease refractory to PIs and immunomodulatory drugs and 64 % had disease refractory to Bortezomib and Lenalidomide), and 76 % had received autologous SCT.  Infusion-related reactions in part 2 were mild (71 % of patients had an event of any grade, and 1 % had an event of grade 3), with no dose-dependent adverse events.  The most common adverse events of grade 3 or 4 (in greater than or equal to 5 % of patients) were pneumonia and thrombocytopenia.  The overall response rate (ORR) was 36 % (95 % confidence interval [CI]: 21.6 % to 52.0 %) in the cohort that received 16 mg/kg (15 patients had a partial response [PR] or better, including 2 with a complete response [CR] and 2 with a very good PR [VGPR]) and 10 % in the cohort that received 8 mg/kg (3 had a PR).  In the cohort that received 16 mg/kg, the median progression-free survival (PFS) was 5.6 months (95 % CI: 4.2 to 8.1), and 65 % (95 % CI: 28 to 86) of the patients who had a response did not have progression at 12 months.  The authors concluded that Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pre-treated and refractory MM.

Lonial et al (2015) reported the findings of an open-label trial evaluating Daratumumab monotherapy in patients with relapsed or refractory MM who had received at least 3 prior lines of therapy including a PI and an immunomodulatory agent or who were double-refractory to a PI and an immunomodulatory agent.  In 106 patients, Daratumumab 16 mg/kg was administered with pre- and post-infusion medication.  Treatment continued until unacceptable toxicity or disease progression.  The median patient age was 63.5 years (range of 31 to 84 years), 49 % were male, and 79 % were Caucasian.  Patients had received a median of 5 prior lines of therapy; 80 % of patients had received prior autologous SCT.  Prior therapies included Bortezomib (99 %), Lenalidomide (99 %), Pomalidomide (63 %), and carfilzomib (50 %).  At baseline, 97 % of patients were refractory to the last line of treatment, 95 % were refractory to both, a PI and an immunomodulatory agent, and 77 % were refractory to alkylating agents.  Efficacy results were based on ORR as determined by the Independent Review Committee assessment using the International Myeloma Working Group (IMWG) criteria.  Overall response rate was 29.2 % (2.8 % stringent CR [sCR], 0 % CR, 9.4 % VGPR, and 10 % PR) (95 % CI: 20.8 % to 38.9 %).  The median time to response was 1 month (range of 0.9 to 5.6 months).  The median duration of response was 7.4 months (range of 1.2 to 13.1+ months).

On November 16, 2015, the Food and Drug Administration (FDA) approved Daratumumab (Darzalex) for the treatment of patients with MM who have received at least 3 prior treatments.  The safety and effectiveness of Darzalex were reported in 2 open-label studies (Lokhorst et al, 2015 and Lonial et al, 2015). This indication was approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The most common side effects of Darzalex were back pain, cough, fatigue, fever, nausea and infusion-related reactions.  Darzalex may also result in anemia, leukopenia, lymphopenia, neutropenia, as well as thrombocytopenia.

The warnings and precautions for Darzalex include infusion reactions, interference with serological testing and interference with determination of complete response. The most frequently reported adverse reactions (incidence ≥20%) were: fatigue, nausea, back pain, pyrexia, cough and upper respiratory tract infection.

In data from three pooled clinical studies including a total of 156 patients, four percent of patients discontinued treatment due to adverse reactions. Infusion reactions were reported in approximately half of all patients treated with Darzalex. Common (≥5 percent) symptoms of infusion reactions included nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnea (shortness of breath) and nausea, severe infusion reactions including bronchospasm, dyspnea, hypoxia and hypertension (<2 percent each).

Darzalex (Daratumumab) has not been evaluated in patients with moderate to severe hepatic impairment. Mild hepatic impairment and renal impairment do not require dosage adjustments.

Darzalex (Daratumumab) can cause severe infusion reactions. Most reactions occur during the first administration. Darzalex (Daratumumab) should be administered with pre‐infusion medications including intravenous corticosteroids, oral antipyretics, and an oral or intravenous antihistamine. An oral corticosteroid should be administered post‐infusion.

Prophylaxis for herpes zoster reaction should be initiated.

Safety and efficacy in pediatric patients has not been established.

Safety and efficacy in pregnancy has not been established.

There is no information regarding the presence of Daratumumab in human milk, the effects on the breastfed infant, or the effects on milk production.

Guidelines on multiple myeloma from the National Comprehensive Cancer Network (NCCN, 2016) recommend Daratumumab for the treatment of patients who have received at least three prior therapies, including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and immunomodulatory agent. 

Experimental Indications:

Lymphoma

Overdijk and colleagues (2015) examined the contribution of antibody-dependent, macrophage-mediated phagocytosis to Daratumumab`s mechanism of action.  Live cell imaging revealed that Daratumumab efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly and sequentially engulfed multiple tumor cells.  Using a range of MM and Burkitt`s lymphoma cell lines, Daratumumab-dependent phagocytosis by mouse and human macrophages was also observed in an in-vitro flow cytometry assay. Phagocytosis contributed to Daratumumab`s anti-tumor activity in-vivo, in both a subcutaneous and an intravenous leukemic xenograft mouse model.  Furthermore, Daratumumab was shown to induce macrophage-mediated phagocytosis of MM cells isolated from 11 of 12 MM patients that showed variable levels of CD38 expression.  The authors concluded that they showed that phagocytosis is a fast, potent and clinically relevant mechanism of action that may contribute to the therapeutic activity of Daratumumab in MM and potentially other hematological tumors.

Wang et al (2015) stated that no standard chemotherapeutic regimens have been defined yet for extra-nodal natural killer/T cell lymphoma (ENKTL), and the prognosis of patients with advanced or relapsed disease is very poor.  Daratumumab has been of great interest in the treatment of CD38-expressing malignancies, especially MM.  In this study, these investigators reviewed the clinical data of 94 patients with ENKTL, investigated the expression of CD38, and analyzed the prognostic value of CD38 expression; 47 patients had weak expression of CD38, and the other 47 patients had strong expression.  The CR rate was significantly higher in patients who were treated with Asparaginase-based therapy (83.8 % versus 59.6 %, p = 0.025).  There was a trend towards higher CR rate in CD38 weak expression group (78.7 % versus 59.6 %, p = 0.074).  At a median follow-up time of 42 months, the 2-year and 5-year PFS rates were 53.0 % and 39.0 %, respectively, and the 2-year and 5-year OS rates were 68.0 % and 58.0 %, respectively.  In multi-variate survival analysis including CD38 expression status, International Prognostic Index (IPI) score, local tumor invasion, and chemotherapeutic regimens, it was found that strong expression of CD38 and non-Asparaginase-based chemo-regimens were independent adverse prognostic factors for PFS (p = 0.009 and 0.027, respectively), while local tumor invasion and higher IPI score were independent adverse prognostic factors for OS (p = 0.002 and 0.035, respectively).  In subgroup analysis, strong expression of CD38 significantly correlated with inferior survival outcomes in patients without local tumor invasion (p = 0.011) or with stage I-II disease (p = 0.008).  The authors concluded that they found that the majority of ENKTL cases were CD38-positive, with 50 % had strong expression of CD38, which significantly correlated with poor outcomes, indicating the potential role of CD38 as a therapy target for ENKTL.

Furthermore, Daratumumab is also being investigated for use in (i) relapsed/refractory mantle cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma, and (ii) smoldering MM.

A phase II clinical trial on “An Efficacy and Safety Proof of Concept Study of Daratumumab in Relapsed/Refractory Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma” is currently recruiting participants (last verified December 2015). 

Smoldering Multiple Myeloma

A phase II clinical trial on “A Study to Evaluate 3 Dose Schedules of Daratumumab in Participants With Smoldering Multiple Myeloma” is currently recruiting participants (last verified December 2015). 

1)    Darzalex Product Information. Janssen Biotech, Inc. Horsham, PA.  September 2019.

2)    Darzalex Faspro Product Information. Janssen Biotech, Inc. Horsham, PA. August 2020.

3)    Clinical Pharmacology. Accessed online 04-09-2021

4)    NCCN Drugs & Biologics Compendium. Accessed online 04-09-2021.

5)    Darzalex FasPro Prescribing Information. Horsham, PA: Janssen Biotceh, Inc.; January 2021.

6)    Kaufman GP, Schrier SL, Lafayette RA, et al. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017; 130(7): 900-902.

7)    Palladini G, Kastritis E, Maurer MS, et al. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood. 2020;136(1):71-80. doi: 10.1182/blood.2019004460.

Addendum:

1)    Effective 01/01/2017: added J9145 as appropriate code for Darzalex

2)    Effective 04/01/2020: Updated for additional coverage criteria for multiple myeloma.

3)    Effective 10/01/2020: Updated to include Darzalex Faspro (C9062) to coverage.

4)    Effective 01/01/2021: Updated code C9062 is being replaced by code J9144.

5)    Effective 06/01/2021: Updated multiple myeloma criteria, added systemic light chain amyloidosis.

6)    Effective 11/01/2023: Updated multiple myeloma criteria and added continued therapy criteria.

This policy applies to all health plans and products administered by QualChoice, both those insured by QualChoice and those that are self-funded by the sponsoring employer, unless there is indication in this policy otherwise or a stated exclusion in your medical plan booklet.  Consult the individual plan sponsor Summary Plan Description (SPD) for self-insured plans or the specific Evidence of Coverage (EOC) or Certificate of Coverage (COC) for those plans or products insured by QualChoice.  In the event of a discrepancy between this policy and a self-insured customer’s SPD or the specific QualChoice EOC or COC, the SPD, EOC, or COC, as applicable, will prevail.  State and federal mandates will be followed as they apply.