Clinical UM Guideline

 

Subject: Elotuzumab (Empliciti™)
Guideline #: CG-DRUG-99 Publish Date:    01/31/2019
Status: Revised Last Review Date:    01/24/2019

Description

This document addresses elotuzumab (Empliciti) (Bristol-Myers Squibb Co., Princeton, NJ), a humanized IgG1 monoclonal antibody. Elotuzumab is FDA-approved in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in individuals who have received one to three prior therapies. It is also FDA-approved in combination with pomalidomide and dexamethasone, in individuals who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. In addition, Elotuzumab is  used in the same population of individuals in combination with bortezomib and dexamethasone. The National Comprehensive Cancer Network (NCCN) supports the use of all 3 triple-drug combination treatments, with elotuzumab plus lenalidomide and dexamethasone as the preferred regimen.

Clinical Indications

Medically Necessary:

The use of elotuzumab is considered medically necessary for the treatment of an individual with relapsed or progressive or refractory multiple myeloma, including plasma-cell leukemia, when prior lines of therapy did not include elotuzumab, and one of the following criteria are met (either A, B, or C):

  1. Elotuzumab is used in combination with lenalidomide and dexamethasone; or
  2. Elotuzumab is used in combination with bortezomib and dexamethasone; or
  3. Elotuzumab is used in combination with pomalidomide and dexamethasone (in individuals who have received at least two prior therapies including lenalidomide and a proteasome inhibitor).

Not Medically Necessary:

The use of elotuzumab is considered not medically necessary when the above criteria are not met, including but not limited to treatment for a diagnosis other than multiple myeloma or plasma-cell leukemia.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J9176

Injection, elotuzumab, 1 mg [Empliciti]

 

 

ICD-10 Diagnosis

 

 

C90.00-C90.32

Multiple myeloma and malignant plasma cell neoplasms

 

Z85.79

Personal history of other malignant neoplasms of lymphoid, hematopoietic and related tissues

 

Discussion/General Information

Multiple myeloma is a systemic malignancy of plasma cells that accumulate in the bone marrow, leading to destruction of bone and failure of the bone marrow. The disease is highly treatable but rarely curable. However, it is potentially curable when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma. Multiple myeloma accounts for approximately 10% of all hematologic cancers. The American Cancer Society has estimated 30,300 new cases of multiple myeloma will be diagnosed in the United States in 2016, with an estimated 12,600 deaths. The stage of the disease at presentation is a strong determinant of survival, but has little influence on the choice of therapy since almost all individuals (except for those with solitary bone tumors or extramedullary plasmacytomas) have generalized disease. Multiple myeloma affects mostly older individuals around 62 years of age. The age and general health of the individual, prior therapy and the presence of complications of the disease influence treatment selection. The median survival in the pre-chemotherapy era was about 7 months. Multiple myeloma has demonstrated chemosensitivity to initial treatment or treatment for relapsed disease. Improvements in newer treatments have resulted in an increase in 5-year survival which is currently around 50%.

Elotuzumab (Empliciti) (Bristol-Myers Squibb Co., Princeton, NJ) is a humanized IgG1 monoclonal antibody that targets the signaling lymphocytic active molecule (SLAM) family member F7 (SLAMF7) protein which is expressed on myeloma cells and natural killer cells. Elotuzumab directly activates natural killer cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on myeloma cells and facilitates the interaction with natural killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity.

The U.S. Food and Drug Administration (FDA) has approved two indications for elotuzumab (Empliciti) to treat adults with multiple myeloma. The first, approved in November 2015, was elotuzumab injection in combination with lenalidomide and dexamethasone in individuals who have received one to three prior therapies. In November 2018, the FDA approved a second indication. This was elotuzumab injection, in combination with pomalidomide and dexamethasone, in individuals who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

For the first indication, the recommended dosage is 10 mg/kg administered intravenously every week for the first two cycles and every 2 weeks thereafter. For the second indication, the recommended dosage is 10 mg/kg administered intravenously every week for the first two cycles and 20 mg/kg every 4 weeks thereafter. For both indications, treatment should continue until disease progression or unacceptable toxicity.

The NCCN Multiple Myeloma Clinical Practice Guideline (V2.2019) recommends elotuzumab in combination with lenalidomide and dexamethasone as a preferred (category 1 recommendation) therapy for individuals with previously treated multiple myeloma. Recommended alternative regimens for this population include elotuzumab in combination with bortezomib, or in combination with pomalidomide and dexamethasone (category 2A recommendations).

Elotuzumab in combination with lenalidomide and dexamethasone

The combination of elotuzumab with lenalidomide and dexamethasone has been studied in 2 randomized controlled trials (RCTs). Richardson and colleagues (2015) reported results of a randomized, multi-center, open-label, dose-escalation study of elotuzumab in combination with lenalidomide and dexamethasone (Study 1703). A total of 73 participants were recruited and randomly assigned to elotuzumab (36 to 10 mg/kg, 37 to 20 mg/kg). Subjects were at least 18 years of age with relapsed multiple myeloma, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and one to three previous therapies, excluding lenalidomide. Treatment consisted of 28-day cycles given until disease progression or unacceptable toxic side effects. At data cutoff in January 2014, 13 subjects continued on treatment (6 subjects on 10 mg/kg and 7 subjects on 20 mg/kg). A total of 61 subjects (84%) achieved an objective response (33 [92%] with 10 mg/kg, 28 [76%] with 20 mg/kg). Thirty-one subjects (42%) had a very good partial response (17 [47%] with 10 mg/kg, 14 [38%] with 20 mg/kg); and 20 (27%) a partial response (10 [28%] with 10 mg/kg, 10 [27%] with 20 mg/kg). Those most common adverse events were diarrhea, muscle spasms and fatigue. Grade 3-4 events occurred in 57 (78%), the most common of which were lymphopenia and neutropenia. Three deaths occurred; however, none were related to the study drugs. The authors concluded that elotuzumab combined with lenalidomide and dexamethasone in subjects with relapsed multiple myeloma showed acceptable safety and efficacy that seemed better than that previously noted with lenalidomide and dexamethasone only.

Findings of the second RCT, known as ELOQUENT-2, were first published in 2015 by Lonial and colleagues.. The open-label trial evaluated the effectiveness and safety of elotuzumab in individuals with relapsed or refractory multiple myeloma who had disease progression after one to three previous therapies. The median number of prior therapies was two, including stem cell transplant (55%), bortezomib (70%), melphalan (65%), thalidomide (48%), and lenalidomide (6%). Prior lines of therapy did not include elotuzumab. Previous treatment with lenalidomide was allowed, subject to restrictions. All subjects had a creatinine clearance of 30 ml per minute or higher. Coprimary endpoints were progression-free survival (PFS) and the overall response rate (partial response or better). A total of 646 subjects were randomized to receive elotuzumab (10 mg/kg) in combination with lenalidomide/dexamethasone (E-Ld) (n=321) or lenalidomide/dexamethasone alone (Ld) (n=325).  

The analysis of ELOQUENT-2 found a statistically significant improvement in median PFS time of 4.5 months between Arm E-Ld (19.4 months) and Arm Ld (14.9 months) and overall response rates of 78.5 and 65.5%, respectively. PFS increased with increasing elotuzumab exposure. The most common adverse reactions were fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, and pneumonia. At the approved dose, 10% of subjects had grade 3 or lower infusion reactions and 1% discontinued elotuzumab due to infusion reactions. Individuals on elotuzumab had increased infections relative to those in the active control group. The rates of grade 3 or higher adverse events or adverse events leading to discontinuations or deaths did not increase with increasing elotuzumab concentration.

Additional follow-up data from the ELOQUENT-2 study were published in 2017 and 2018 by Dimopoulos and colleagues. Three-year PFS was 26% in Arm E-Ld arm and 18% in Arm Ld, with a hazard ratio (HR) of 0.73; 95% confidence interval (CI) of 0.60-0.89, p=0.0014, indicating a sustained benefit of elotuzumab (Dimopoulos, 2017). Overall survival (OS) was a secondary outcome of the study. OS after a minimum of 36 months of follow-up (median follow-up=38.7 months) was 43.7 months in Arm E-Ld and 39.6 months in Arm Ld (p=0.026). OS rates in Arm E-Ld versus Arm Ld were 91% and 83% at 1 year, 73% and 69% at 2 years and 60% and 53% at 3 years. The authors noted sustained separation over time in Kaplan-Meier survival curves.

After 4 years of follow-up, PFS was 21% in Arm E-Ld and 14% in Arm Ld. The HR significantly favored the E-Ld group (HR: 0.71, 95% CI: 0.59-0.86, p=0.004) (Dimopoulos, 2018a). The 4-year OS rate was 50% in Arm E-Ld and 43% in Arm Ld. The difference in OS between groups was statistically significant, HR: 0.78 (95% CI: 0.63-0.96, p-value not reported).

Elotuzumab in combination with pomalidomide and dexamethasone

One open-label RCT, known as ELEQUENT-3, evaluated the combination of elotuzumab plus pomalidomide and dexamethasone for treatment of refractory or relapsed and refractory multiple myeloma (Dimopoulos, 2018b). The study included 117 individuals who had received 2 or more previous lines of therapy, including at least 2 consecutive cycles of lenalidomide and a protease inhibitor. Participants were randomly assigned to receive pomalidomide and dexamethasone only (n=57) or with the addition of elotuzumab (n=60). The primary endpoint was PFS and analysis was intention-to-treat. Secondary outcomes included the overall response rate and OS. The analysis occurred after a minimum follow-up period of 9.1 months.

Median PFS was 10.3 months (95% CI: 5.6 months to not reached) in the group receiving elotuzumab and 4.7 months (95% CI: 2.8 to 7.2 months) in the control group. PFS was significantly higher in the elotuzumab group than the control group (HR: 0.54, 95% CI: 0.34-0.86, p=0.008). The overall response rate, assessed by an independent review committee, was 58% (95% CI: 45-71%) in the elotuzumab group and 25% (95% CI: 14-38%) in the control group, significantly favoring the elotuzumab group (odds ratio [OR]: 4.62, 95% CI: 2.05-10.43). The investigators determined that there was insufficient data to compare OS in the 2 groups at the time of data analysis. The rate of Grade 3 or 4 adverse events was similar in the 2 groups, 57% in the elotuzumab group and 60% in the control group. The most common adverse events were neutropenia, anemia, hyperglycemia and infections.

Elotuzumab in combination with bortezomib and dexamethasone

One RCT has evaluated elotuzumab in combination with bortezomib and dexamethasone (EBd) for the treatment of relapsed/refractory multiple myeloma.  This study, by Jakubowiak and colleagues (2016), was a proof-of-concept open-label, phase II trial. A total of 152 individuals with relapsed/refractory multiple myeloma (RRMM) were randomized to receive either elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included overall response rate and OS. Individuals were eligible if they were at least 18 years of age or older with a confirmed diagnosis of multiple myeloma, documented disease progression after 1 to 3 prior lines of therapy, ECOG performance status of at least 2, confirmed disease progression during or after most recent therapy, and measurable disease. A total of 150 of the original 152 subjects were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 95% CI, 0.59-0.88; stratified log-rank P=0.09). Median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In the updated analysis based on 60 deaths, the 2-year OS rate was 73% (95% CI, 61%-82%) with EBd versus 66% (95% CI, 54%-76%) with Bd. Follow-up for OS continues. Minimal differences were noted in adverse events between study arms. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. The authors concluded that the addition of elotuzumab resulted in a longer PFS compared to BD alone and was well tolerated.

Definitions

Line of therapy:

Monoclonal antibody: A type of protein made in the laboratory that can bind to substances in the body, including cancer cells. There are many kinds of monoclonal antibodies. A monoclonal antibody is made so that it binds to only one substance. Monoclonal antibodies are being used to treat some types of cancer. They can be used alone or to carry drugs, toxins, or radioactive substances directly to cancer cells.

Plasma cell leukemia: A rare and aggressive form of multiple myeloma characterized by high levels of plasma cells in the peripheral blood.

Progressive disease: For cancer, disease that is growing (e.g. growth in size of tumor), spreading, or worsening.

Proteasome inhibitors: A class of drugs used to treat multiple myeloma that work by blocking the action of proteasomes which are cellular complexes that break down proteins. Examples include bortezomib, carfilzomib and ixazomib.

Refractory disease: Illness or disease that does not respond to treatment.

Relapse: After a period of improvement, the return of signs and symptoms of cancer.

References

Peer Reviewed Publications:

  1. Dimopoulos MA, Lonial S, White D et al. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017;178(6):896-905.
  2. Dimopoulos MA, Lonial S, Betts KA, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018a; 124(20):4032-4043.
  3. Dimopoulos MA, Dytfeld D, Grosicki S et al. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. N Engl J Med. 2018b; 379(19):1811-1822.
  4. Jakubowiak A, Offidani M, Pégourie B, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016; 127(23):2833-2840.
  5. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015; 373(7):621-631.
  6. Richardson PG, Jagannath S, Moreau P, et al; 1703 study investigators. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015; 2(12):e516-527.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Empliciti [Product Information]. Princeton, NJ. Bristol-Myers Squibb Co., Princeton, NJ. Revised November 2018. Available at: http://packageinserts.bms.com/pi/pi_empliciti.pdf. Accessed on November 21, 2018.
  2. NCCN Clinical Practice Guidelines in Oncology®. © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on March 21, 2018.
    • Multiple Myeloma (V.2.2019). Revised November 16, 2018.
Websites for Additional Information
  1. American Cancer Society. Chemotherapy and Other Drugs for Multiple Myeloma. Available at: https://www.cancer.org/cancer/multiple-myeloma/treating/chemotherapy.html. Accessed on November 26, 2018.
  2. National Cancer Institute. Elotuzumab. Available at: https://www.cancer.gov/about-cancer/treatment/drugs/elotuzumab. Accessed on November 26, 2018.
Index

Elotuzumab
Empliciti

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Revised

01/24/2019

Medical Policy & Technology Assessment Committee (MPTAC) review

Revised

01/16/2019

Hematology/Oncology Subcommittee review. Added bullet point to medically necessary statement on elotuzumab used in combination with pomalidomide and dexamethasone. Updated Description, Clinical Indications, Discussion/General Information, Definitions and References sections.

New

05/03/2018

MPTAC review

New

05/02/2018

Hematology/Oncology Subcommittee review. Initial document development. Moved content of DRUG.00083 Elotuzumab (Empliciti) to new clinical utilization management guideline document with the same title. Updated Discussion/General Information and References sections.