Elotuzumab (Empliciti)

Number: 0899

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of elotuzumab is required of all Aetna participating providers and members in applicable plan designs.  For precertification of elotuzumab, call (866) 752-7021, or fax (866) 267-3277.

Aetna considers elotuzumab (Empliciti) medically necessary for the treatment of multiple myeloma when all of the following criteria are met: 

• The disease is relapsed or progressive; and
• Elotuzumab (Empliciti) will be used in any of the following regimens:
  
  
  • In combination with lenalidomide and dexamethasone in persons who have received 1 to 3 prior therapies; or
  • In combination with bortezomib and dexamethasone in members who have received at least one prior therapy; or
  • In combination with pomalidomide and dexamethasone in persons who have received at least two prior therapies, including an immunomodulatory agent and a proteasome inhibitor.

Aetna considers continued treatment with elotuzumab medically necessary in members requesting reauthorization for a medically necessary indication who have not experienced unacceptable toxicity or disease progression while on the current regimen.

Aetna considers elotuzumab experimental and investigational for all other indications including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:

• B-cell lymphoma (including lymphoplasmacytic lymphoma)
• Newly diagnosed (not previously treated) multiple myeloma
• Non-Hodgkin lymphoma (including diffuse large B-cell lymphoma, follicular lymphoma, indolent B-cell lymphoma, mantle-cell lymphoma, and primary mediastinal lymphoma)
• Primary amyloidosis
• Smoldering multiple myeloma.

Dosing Recommendations

Elotuzumab is available as Empliciti in 300 mg and 400 mg vials. Recommended dosing is:

Elotuzumab with lenalidomide and dexamethasone: 10 mg/kg administered intravenously every week for the first 2 cycles and every 2 weeks thereafter until disease progression or unacceptable toxicity.  Pre-medicate with dexamethasone, diphenhydramine, ranitidine and acetaminophen.

Elotuzumab with pomalidomide and dexamethasone: 10 mg/kg administered intravenously every week for the first two cycles and 20 mg/kg every 4 weeks thereafter until disease progression or unacceptable toxicity.  Pre-medicate with dexamethasone, diphenhydramine, ranitidine and acetaminophen.

Source: Bristol-Myers Squibb Company, 2018

Background

Multiple myeloma (MM) is characterized by the neoplastic proliferation of clonal plasma cells in the bone marrow resulting in skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. Additional disease-related complications include hypercalcemia, renal insufficiency, anemia, and infections.

Schmidt-Wolf and colleagues (2014) stated that MM, with an incidence of 4 to 6/100,000 inhabitants, is a fairly frequent malignancy of B cells.  The incidence increases markedly with age. While standard treatments are associated with high response rates in patients with newly diagnosed multiple myeloma (MM), effective therapy for relapsed and refractory patients remains a challenge. The present standard of care in the 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 therapy with stem cell transplantation is recommended in fit patients up to 75 years without significant co-morbidities.  Ongoing studies address the question about the least toxic and the most effective treatment.  Therefore, inclusion of patients in therapeutic trials and use of novel agent combinations is highly recommended including the use of 3rd generation immunomodulatory drugs (IMIDs; e.g., pomalidomide), new proteasome inhibitors (e.g., carfilzomib, ixazomib or oprozomib), antibodies (e.g., daratumumab, denosumab, elotuzumab, romosozumab, siltuximab, tabalumab), Bruton's tyrosine kinase (BTK)-, heat shock protein (HSP)-inhibitors and other innovative phase I/II agents.

Ashjian and Redic (2016) noted that there have been a number of recent advances in the treatment of patients with relapsed and refractory MM.  However, despite additional Food and Drug Administration (FDA)-approved therapies including carfilzomib and pomalidomide as well as clinical trials investigating new combinations of existing treatments, MM remains an incurable disease.  New therapies currently in the drug development pipeline for relapsed and refractory MM include additional proteasome inhibitors (ixazomib, marizomib, oprozomib), histone deacetylase inhibitors (panobinostat, quisinostat, ricolinostat), mAbs (daratumumab, elotuzumab), BTK inhibitors (ibrutinib) and others.

On November 30, 2015, the FDA approved elotuzumab (Empliciti) in combination with lenalidomide and dexamethasone to treat people with MM who have received 1 to 3 prior medications.  The FDA approval was based on the findings of the phase III clinical trial by Lonial et al (2015).  The most common side effects of Empliciti are constipation, cough, diarrhea, fatigue, nasopharyngitis, pneumonia, pyrexia, decreased appetite, peripheral neuropathy, and upper respiratory tract infection.

Lonial and associates (2013) reviewed the scientific literature regarding the development and clinical investigation of a CS1-targeted monoclonal antibody (mAb), elotuzumab, for the potential treatment of MM.  Elotuzumab is an immunostimulatory mAb targeting signaling lymphocytic activation molecule F7 (SLAMF7). This binding triggers the interactions of natural killer T cells to mediate the destruction of myeloma cells via the antibody dependent cellular cytotoxicity process. The authors summarized the pre-clinical pharmacological data, along with safety, tolerability and effectiveness of elotuzumab alone and in combination. They stated that elotuzumab, in combination with lenalidomide, showed high overall response rate (ORR) in phase I and II clinical trials.  Furthermore, the improvements observed in progression-free survival (PFS) suggested superiority over lenalidomide/dexamethasone alone, with a similar tolerability profile.  These researchers noted that while elotuzumab is associated with a higher incidence of infusion reactions, these can be managed with appropriate pre-medication.  The authors noted that the high activity of the elotuzumab/lenalidomide combination is being further investigated in phase III clinical trials.  They stated that elotuzumab represents an exciting potential therapeutic option for patients with MM, including those with relapsed and refractory disease, as well as in the induction and post-transplant maintenance settings, and possibly even for early therapy in patients with high-risk smoldering myeloma.

In a phase III, multi-center, randomized controlled trial (RCT), Lonial and colleagues (2015) randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group).  Co-primary end-points were PFS and the ORR.  Final results for the co-primary end-points were reported on the basis of a planned interim analysis of PFS.  Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group.  After a median follow-up of 24.5 months, the rate of PFS at 1 year in the elotuzumab group was 68 %, as compared with 57 % in the control group; at 2 years, the rates were 41 % and 27 %, respectively.  Median PFS in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio [HR] for progression or death in the elotuzumab group, 0.70; 95 % confidence interval [CI]: 0.57 to 0.85; p < 0.001).  The ORR in the elotuzumab group was 79 %, versus 66 % in the control group (p < 0.001).  Common grade 3 or 4 adverse events in the 2 groups were fatigue, lymphocytopenia, neutropenia, and pneumonia.  Infusion reactions occurred in 33 patients (10 %) in the elotuzumab group and were grade 1 or 2 in 29 patients.  The authors concluded that patients with relapsed or refractory MM who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30 % in the risk of disease progression or death.

On November 06, 2018, the FDA approved elotuzumab (Empliciti) in combination pomalidomide and dexamethasone (EPd) for the treatment of adult patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. This approval was based on results from ELOQUENT-3, a randomized, open-label, Phase 2 trial where EPd demonstrated benefit in patients with relapsed or refractory multiple myeloma, doubling both median progression-free survival (PFS) and overall response rate (ORR) versus pomalidomide and dexamethasone (Pd) (NCT02654132; Dimopoulos et al 2018).

Dimopoulos et al (2018) stated the  immunostimulatory monoclonal antibody elotuzumab plus lenalidomide and dexamethasone has been shown to be effective in patients with relapsed or refractory multiple myeloma. The immunomodulatory agent pomalidomide plus dexamethasone has been shown to be effective in patients with multiple myeloma that is refractory to lenalidomide and a proteasome inhibitor. Patients with multiple myeloma that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor were randomly assigned to receive elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone alone (control group). The primary end point was investigator-assessed progression-free survival. A total of 117 patients were randomly assigned to the elotuzumab group (60 patients) or the control group (57 patients). After a minimum follow-up period of 9.1 months, the median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group. The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval [CI], 0.34 to 0.86; P=0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11). The most common grade 3 or 4 adverse events were neutropenia (13% in the elotuzumab group vs. 27% in the control group), anemia (10% vs. 20%), and hyperglycemia (8% vs. 7%). A total of 65% of the patients in each group had infections. Infusion reactions occurred in 3 patients (5%) in the elotuzumab group. The authors concluded that among patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor had failed, the risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-3 ClinicalTrials.gov number, NCT02654132).

Warnings and Precautions

• Infusion related reactions: Empliciti (elotuzumab) can cause infusion related reactions. Majority of the infusion related reactions occur with the first administration. Empliciti (elotuzumab) should be administered with pre‐infusion medications including intravenous corticosteroids, oral antipyretics, and an oral or intravenous anthistamine.
• Infections: Infections were reported in majority of patients. Patients should be monitored for infections accordingly and treated immediately.
• Second primary tumors: Second primiary tumors have been reported in the clinical trials. Patients should be monitored for the development of second primary tumors.
• Hepatotoxicity: Elevations in transaminases have been reported in clinical trials. Patients should have liver enzymes monitored routinely. Interrupt Empliciti (elotuzumab) therapy if liver enzymes are Grade 3 or higher.
• Safety and efficacy in pregnancy has not been evaluated.
• There is no information concerning presence of Empliciti (elotuzumab) in human milk, the outcomes on breastfed infant, or the outcomes on production of milk.
• Safety and efficacy in pediatric patients has not been evaluated.

Experimental Indications

There are 2 clinical trials on elotuzumab for the treatment of other malignancies --

1. a phase-I trial: “Ph I Trial of NAM NK Cells and IL-2 for Adult Pts With MM and NHL” (This study is not yet open for participant recruitment; last verified January 2017); and
2. a phase-II trial: “Lenalidomide, Dexamethasone, and Elotuzumab With or Without Cyclophosphamide in Treating Patients With Relapsed Primary Amyloidosis” (This study is currently recruiting participants; last verified September 2017).

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) does not list elotuzumab for any indication except for multiple myeloma.

Newly Diagnosed Multiple Myeloma

Radhakrishnan and associates (2017) stated that treatment of MM has undergone significant change in the past 10 years with the introduction of new immunomodulatory agents, proteasome inhibitors, and immunotherapeutic approaches.  Elotuzumab is a humanized monoclonal antibody targeting CS1, which is a member of the SLAM (Signaling Lymphocyte Activation Molecule) family of proteins, expressed on the surface of myeloma plasma cells.  These investigators reviewed the pre-clinical investigations that led to the development of elotuzumab and the clinical studies that resulted in its approval for the treatment of relapsed/refractory MM.  Although pre-clinical data looked very promising, elotuzumab monotherapy did not result in objective clinical responses in patients with relapsed/refractory multiple myeloma.  However, combination treatment with immunomodulators and proteasome inhibitors resulted in substantial clinical activity in relapsed/refractory MM.  The authors concluded that ongoing clinical trials are examining the role of elotuzumab in newly diagnosed MM in combination with standard treatment as well as in the maintenance setting after autologous stem cell transplant.

Smoldering Multiple Myeloma

Smoldering multiple myeloma is an asymptomatic clonal plasma cell disorder (Rajkumar, et al., 2015). Smoldering multiple myeloma is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma.

Jagannath and colleagues (2018) noted that smoldering MM (SMM) is associated with increased risk of progression to MM within 2 years, with no approved treatments.  Elotuzumab has been shown to promote natural killer (NK) cell stimulation and antibody-dependent cellular cytotoxicity (ADCC) in-vitro.  CD56dim (CD56dim /CD16+ /CD3- /CD45+ ) NK cells represent the primary subset responsible for elotuzumab-induced ADCC.  In a phase-II, non-randomized clinical trial, patients with SMM received elotuzumab 20 mg/kg intravenously (cycle 1: days 1, 8; monthly thereafter) or 10 mg/kg (cycles 1, 2: weekly; every 2 weeks thereafter).  The primary end-point was the relationship between baseline proportion of bone marrow-derived CD56dim NK cells and maximal M protein reduction; secondary end-points included ORR and PFS.  A total of 15 patients received 20 mg/kg and 16 received 10 mg/kg; combined data were presented.  At database lock (DBL, September 2014), no association was found between baseline CD56dim NK cell proportion and maximal M protein reduction.  With minimum 28 months' follow-up (DBL: January 2016), ORR (90 % CI) was 10 % (2.7 to 23.2) and 2-year PFS rate was 69 % (52 to 81 %).  Upper respiratory tract infections occurred in 18/31 (58 %) patients; 4 (13 %) patients experienced infusion reactions, all grade 1 to 2.  The authors stated that elotuzumab plus lenalidomide/dexamethasone is under investigation for SMM.

National Comprehensive Cancer Network (NCCN) Recommendations

The NCCN Drugs and Biologics Compendium (NCCN, 2019) recommends elotuzumab] for the following:

Therapy for previously treated multiple myeloma for relapse or progressive disease in combination with [1 for combination with lenalidomide and dexamethasone; 2A for all others]

• lenalidomide and dexamethasone in patients who have received one to three prior therapies (preferred regimen)
• bortezomib and dexamethasone
• pomalidomide and dexamethasone in patients who have received at least two prior therapies, including an immunomodulatory agent and a proteasome inhibitor.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
HCPCS codes covered if selection criteria are met :
Elotuzumab (Empliciti) :
HCPCS codes covered if selection criteria are met:
J9176	Injection, elotuzumab, 1 mg
Other HCPCS codes related to the CPB:
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1mg
J8540	Dexamethasone, oral, 0.25 mg
J9041	Injection, bortezomib, 0.1 mg
J9047	Injection, carfilzomib, 1 mg
ICD-10 codes covered if selection criteria are met:
C90.02	Multiple myeloma in relapse
ICD-10 codes not covered for indications listed in the CPB:
C82.00 - C82.09	Follicular lymphoma
C83.00 - C83.09	Small cell B-cell lymphoma
C83.10 - C83.19	Mantle-cell lymphoma
C83.30 - C83.39	Diffuse large B-cell lymphoma
C83.50 - C83.59	Lymphoplasmacytic diffuse lymphoma
C85.10 - C85.99	Other and unspecified types of non-Hodgkin lymphoma
C90.00 - C90.01	Multiple myeloma not having achieved remission and in remission [not covered for newly diagnosed multiple myeloma and smoldering multiple myeloma]
E85.0 - E85.9	Amyloidosis

The above policy is based on the following references: