Medical Policy



Subject: Elotuzumab (Empliciti™)
Document #: DRUG.00083 Current Effective Date:    05/18/2017
Status: Revised Last Review Date:    05/04/2017

Description/Scope

This document addresses elotuzumab (Empliciti) (Bristol-Myers Squibb Co., Princeton, NJ), 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.

Position Statement

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 or B):

  1. Elotuzumab is used in combination with lenalidomide and dexamethasone; or
  2. Elotuzumab is used in combination with bortezomib and dexamethasone.

Investigational and Not Medically Necessary:

The use of elotuzumab is considered investigational and 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.

Rationale

On November 30, 2015, the U.S. Food and Drug Administration (FDA) granted approval to elotuzumab (Empliciti) injection in combination with lenalidomide and dexamethasone for the treatment of individuals with multiple myeloma who have received one to three prior therapies. The approved recommended dosage is 10 mg/kg, administered as an intravenous infusion, weekly on weeks 1 to 8 and every 2 weeks from week 9 until disease progression or unacceptable toxicity. This application was granted priority review and had both orphan drug and breakthrough therapy designations.

Richardson and colleagues (2015) reported final phase II results of a randomized, multi-center, open-label, dose-escalation study of elotuzumab in combination with lenalidomide and dexamethasone (Study 1703). Between January 2010, and December 2010, 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.

A single randomized phase III, controlled, open-label, multi-center trial (ELOQUENT-2) (Lonial, 2015) 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 final analysis showed 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.

Jakubowiak and colleagues (2016) conducted a proof-of-concept open-label, phase II trial that studied effects of adding elotuzumab to bortezomib and dexamethasone (EBd) for the treatment of relapsed/refractory multiple myeloma. 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 (ORR) and overall survival (OS). Individuals were eligible if they were at least 18 years of age or older with a confirmed diagnosis of MM, documented disease progression after one to three prior lines of therapy, ECOG performance status of at least 2, confirmed disease progression during or after most recent therapy, and measurable disease. Demographics were similar across both treatment groups. A total of 150 of the original 152 subjects were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (hazard ratio [HR], 0.72; 70% confidence interval [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 overall survival 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.

The National Comprehensive Cancer Network (NCCN) Multiple Myeloma Clinical Practice Guideline (V3.2017) and the NCCN Drugs and Biologics Compendium indicate that elotuzumab is recommended in combination with lenalidomide and dexamethasone (preferred) (category 1 recommendation) or in combination with bortezomib and dexamethasone (category 2A recommendation) for the treatment of individuals with relapsed or progressive or refractory multiple myeloma who have received one to three prior therapies.

Background/Overview

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. Multiple myeloma is highly treatable but rarely curable. However, when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma it is potentially curable. 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%.

Contraindications, Warnings, Precautions and Adverse Events (Empliciti Prescribing Information, 2015)

Contraindications

Warnings and Precautions

Adverse Reactions

Common adverse reactions (20% or higher) are fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, pneumonia.

Use In Specific Populations

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. (NCI, 2016)

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

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.

Coding

The following codes for treatments and procedures applicable to this document 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.

When services may be Medically Necessary when criteria are met:

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  

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. 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.
  2. 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.
  3. 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. Elotuzumab Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised September 12, 2016. Accessed on March 16, 2017.
  2. Elotuzumab (systemic). In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated November 16, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 16, 2017.
  3. Empliciti™ [Product Information]. Princeton, NJ. Bristol-Myers Squibb Co., Princeton, NJ. November 2015. Available at: http://packageinserts.bms.com/pi/pi_empliciti.pdf. Accessed on March 16, 2017.
  4. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on March 16, 2017.
  5. 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 16, 2017.
    • Multiple Myeloma (V.3.2017). Revised November 28, 2016.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org. Accessed on March 16, 2017.
  2. National Cancer Institute. Available at: http://www.cancer.gov. Accessed on March 16, 2017.
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.

Document History
Status Date Action
Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Revised 05/03/2017 Hematology/Oncology Subcommittee review. Formatting updated in Position Statement section. Medically Necessary statement updated to include use in combination with bortezomib and dexamethasone. Clarified Investigational and NMN statement by replacing "including" with "or". Rationale, Background, References and Websites sections updated.
  01/01/2017 Updated Coding section with 01/01/2017 HCPCS changes; removed code C9477 deleted 12/31/2016.
New 05/05/2016 MPTAC review.
New 05/04/2016 Hematology/Oncology Subcommittee review. Initial document development.