Empliciti (Elotuzumab): First SLAMF7 Antibody Therapy Approved for the Treatment of Patients with Previously Treated Multiple Myeloma

2016 Oncology Pharmacy Guide to New FDA Approvals - Drug Profiles
Lisa A. Raedler, PhD, RPh, Medical Writer

 

Multiple myeloma is a cancer of plasma cells in the bone marrow that often leads to bone destruction and bone marrow failure.1,2 According to the American Cancer Society, more than 26,800 new cases of multiple myeloma were diagnosed in 2015, and 11,240 deaths were attributed to the disease.3

Representing approximately 1% of all cancers, multiple myeloma is the second most common hematologic malignancy after non-Hodgkin lymphoma.4 The incidence of multiple myeloma is higher among men than among women.1 Individuals aged ≥65 years, those with a family history of multiple myeloma, and those with a personal history of monoclonal gammopathy of undetermined significance are at an increased risk for multiple myeloma.1 Several common complications of multiple myeloma include bone pain, kidney dysfunction, bone loss, impaired immunity, and anemia.5

Although the overall incidence of multiple myeloma continues to increase, the mortality rates associated with this malignancy have declined in the past 20 years.1,6 Specifically, the advent of novel therapeutic options for multiple myeloma, as well as improvements in high-dose therapy and supportive care have contributed to extended survival for this patient population.6

New anticancer drugs and novel combinations have emerged in part as a result of improved understanding of the bone marrow microenvironment and the biology of multiple myeloma.7 Immunomodulators and proteasome inhibitors now represent the cornerstones of initial treatment for multiple myeloma based on their proved ability to enhance the overall response rates and survival.2,7

Because novel agents for multiple myeloma have had a considerable impact on the healthcare budget, understanding their relative cost-effectiveness is important for ensuring efficient use. Overall, 2 recent evaluations of the economics of these new agents in multiple myeloma resulted in similar conclusions.8,9

One of the studies used claims data from more than 2600 US-based patients with multiple myeloma, and found that the 1-year costs of bortezomib-based therapy were similar to the costs of non-novel combinations (approximately $112,000 each), whereas the costs of thalidomide- and lenalidomide-based regimens were significantly higher (approximately $130,500 and $159,200, respectively) than non-novel combinations.8 This study also found that patients taking thalidomide and lenalidomide had higher out-of-pocket costs in light of Medicare Part D’s coverage gap for outpatient drugs.8

The second study modeled the cost-effectiveness of novel agents combined with melphalan and prednisone in patients with newly diagnosed multiple myeloma who were ineligible for a transplantation.9 The researchers concluded that adding bortezomib to melphalan and prednisone was more cost-effective than adding thalidomide or lenalidomide to that regimen.9

Despite strides in the treatment of multiple myeloma, patients will experience disease relapse after initial treatment and multiple lines of therapy are typically required.10

Treatment considerations for patients with relapsed and/or refractory multiple myeloma include the duration of response to previous treatment and the risk for toxicity. Therefore, there is a marked need for additional therapeutic options for this patient population.10

Elotuzumab Second Monoclonal Antibody Approved for Relapsed Multiple Myeloma

On November 30, 2015, the US Food and Drug Administration (FDA) approved elotuzumab (Empliciti; Bristol-Myers Squibb) for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received 1 to 3 previous therapies.11

Elotuzumab is the first monoclonal antibody that targets the signaling lymphocytic activation molecule family (SLAMF) 7 protein, and the second monoclonal antibody approved for patients with relapsed multiple myeloma.11 The approval of elotuzumab was based on a 2-year analysis of the ELOQUENT-2 study, a randomized phase 3 clinical trial that showed a 30% improvement in progression-free survival (PFS) when elotuzumab was added to lenalidomide and dexamethasone compared with lenalidomide plus dexamethasone alone.11-13

Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, said, “We are continuing to learn about the ways the immune system interacts with different types of cancer, including multiple myeloma. Today’s approval is the second monoclonal antibody approved to treat patients with multiple myeloma and works with another approved therapy to provide additional benefit.”11

Mechanism of Action

Elotuzumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that specifically targets the SLAMF7 protein. SLAMF7 is a receptor present on immune cells, including natural killer cells, plasma cells, and specific immune-cell subsets of differentiated cells within the hematopoietic lineage. Elotuzumab is also expressed on multiple myeloma cells regardless of cytogenetic abnormalities.12

Elotuzumab directly activates natural killer cells through the SLAMF7 pathway and Fc receptors on immune cells. Elotuzumab targets SLAMF7 on multiple myeloma cells and facilitates interactions with natural killer cells to mediate the killing of tumor cells through antibody-dependent cellular cytotoxicity.12

Dosing and Administration

The recommended dose of elotuzumab, when given in conjunction with lenalidomide and low-dose dexamethasone, is 10 mg/kg via intravenous infusion weekly for the first 2 cycles and every 2 weeks thereafter until disease progression or until unacceptable toxicity. Treatment with the elotuzumab-based regimen should be continued until disease progression or until unacceptable toxicity.12

Patients should be premedicated with 4 agents, including dexamethasone; an H1 blocker, such as diphenhydramine; an H2 blocker, such as ranitidine; and ­acetaminophen given 45 to 90 minutes before the elotuz­umab infusion.12

Elotuzumab is available in 300-mg and 400-mg vials, each with a postreconstitution dilution of 25 mg/mL.12

Clinical Trials: ELOQUENT-2

The efficacy and safety of elotuzumab were demonstrated in the ELOQUENT-2 study, a multinational, randomized, open-label, phase 3 study comparing elotuz­umab plus lenalidomide and low-dose dexamethasone with lenalidomide plus low-dose dexamethasone in patients with multiple myeloma who had received 1 to 3 previous therapies, and who had documented disease progression after their most recent therapy.11-13

A total of 646 patients were randomized to the elotuz­umab-based regimen (N = 321) or to lenalidomide plus low-dose dexamethasone alone (N = 325) in 4-week treatment cycles until disease progression or until unacceptable toxicity. Patients randomized to the elotuzu­mab-based regimen received elotuzumab (10 mg/kg intravenously) weekly for the first 2 cycles, followed by every 2 weeks for subsequent cycles. Tumor response assessments were conducted every 4 weeks.12

The primary efficacy end points in ELOQUENT-2 included progression-free survival as assessed by hazard ratio (HR) and overall response rate as determined by a blinded Independent Review Committee using the European Group for Blood and Marrow Transplantation response criteria.12

The demographic and baseline characteristics were similar between the 2 treatment arms in the ELOQUENT­2 trial. The majority of patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 (91%). The patients’ median age was 66 years (range, 37-91 years).12

The majority (75%) of patients enrolled in ELOQUENT-2 had stage I or stage II multiple myeloma according to the International Staging System; 21% of patients had stage III disease. Cytogenetic abnormalities of deletion 17p and t(4;14) were documented in 32% and 9% of patients, respectively.12

Patients received a median of 2 previous therapies, including bortezomib (70%), stem-cell transplantation (55%), melphalan (65%), thalidomide (48%), and lenalidomide (6%).12 Overall, 65% of patients had relapsed multiple myeloma (ie, disease that progressed after more than 60 days from their last therapy), and 35% of patients had disease that was refractory to their previous regimen.12

The PFS and overall response rates were significantly improved in patients with relapsed and/or refractory multiple myeloma who received the elotuzumab-based regimen compared with patients who received lenalidomide plus low-dose dexamethasone alone (Table 1).12

Table 1

The median PFS was 19.4 months among the elotuz­umab-based regimen cohort compared with 14.9 months for the lenalidomide plus dexamethasone group, a significant difference (HR, 0.70; 95% confidence interval, 0.57-0.85; P = .004).12 After 2 years, 41% of patients had PFS in the elotuzumab-based arm, and 27% of patients had PFS in the lenalidomide plus dexamethasone arm.12

The overall response rate in the elotuzumab-based arm was 79% compared with 66% in the lenalidomide plus dexamethasone group, representing a significant difference (P = .002).12

The extended 3-year follow-up data from ELOQUENT-2 demonstrated that the elotuzumab-based regimen delayed the need for subsequent therapy by a median of 1 year compared with lenalidomide plus dexamethasone alone.14,15 The prespecified interim analysis of the overall survival data showed a positive trend in favor of the elotuzumab-based regimen, but the results did not reach significance. Patients in the ELOQUENT-2 trial will continue to be followed.14,15

Adverse Events

Patients in the elotuzumab-containing arm of the ELOQUENT-2 study received a median of 19 treatment cycles compared with 14 treatment cycles in the lenalidomide plus dexamethasone group (minimum follow-up, 2 years).12

The proportion of patients who discontinued any component of their treatment regimen because of adverse reactions was similar in both arms: 6.0% for patients in the elotuzumab arm, and 6.3% for patients in the lenalidomide plus dexamethasone arm.12

Serious adverse reactions were reported in 65% of patients who received the elotuzumab-based regimen, and in 57% of patients who received lenalidomide plus dexamethasone.12 The most frequent serious adverse reactions in the elotuzumab arm compared with the lenalidomide plus dexamethasone arm included pneumonia (15% vs 11%, respectively), pyrexia (7% vs 5%), pulmonary embolism (3% in both arms), acute renal failure (3% vs 2%), anemia (3% vs 2%), and respiratory tract infection (3% vs 1%).12

Adverse reactions (all grades) occurring at a frequency of ≥25% in the elotuzumab arm, and ≥5% in patients receiving lenalidomide plus dexamethasone included fatigue or asthenia (62% vs 52%, respectively); diarrhea (47% vs 36%); pyrexia (37% vs 25%); constipation (36% vs 27%); cough, including grouped terms (34% vs 19%); peripheral neuropathy, including grouped terms (27% vs 21%); and nasopharyngitis (25% vs 19%).12

Laboratory abnormalities (grade 3 or 4) that occurred at a frequency of ≥15% in the elotuzumab arm and at a rate of ≥5% more than in patients receiving lenalidomide plus dexamethasone included lymphopenia (77% vs 49%, respectively), leukopenia (32% vs 26%), and hyperglycemia (17% vs 10%).12

Vital sign abnormalities were assessed in the treatment arm cohort in the ELOQUENT-2 study (Table 2). The data reflect the percent of patients with at least 1 on-treatment vital sign abnormality at any time during their course of treatment.12

Table 2

Elotuzumab has no contraindications.12

Warnings and Precautions

Infusion reactions. Grade 1, 2, or 3 infusion reactions were reported in approximately 10% of patients who received elotuzumab, most often during the first dose. Grade 3 infusion reactions occurred in 1% of patients, and 1% of patients discontinued elotuzumab because of infusion reactions.12

Premedications should be administered before each elotuzumab infusion. If a grade ≥2 infusion reaction occurs, the infusion should be interrupted and medical management should be instituted.12

Infections. Infections were reported in 81% of patients receiving elotuzumab; treatment discontinuations because of infections occurred in 3.5% of patients in the elotuzu­mab arm. Patients should be monitored for infections.12

Second primary malignancies. Invasive second primary malignancies were reported in 9% of patients receiving elotuzumab. Patients should be monitored for second malignancies.12

Hepatotoxicity. Elevations in liver enzymes consistent with hepatotoxicity were reported in 2.5% receiving elotuzumab. Overall, 6 of 8 patients were able to continue treatment with elotuzumab after their hepatotoxicity had resolved. Elotuzumab should be discontinued if grade ≥3 liver enzymes elevations occur, and can be reinitiated after values return to baseline.12

Interference with determination of complete response. Elotuzumab, a humanized IgG kappa monoclonal antibody, can be detected on serum protein electrophoresis and immunofixation assays used to monitor endogenous M-protein levels. The determination of complete response and disease progression can be affected in patients with IgG kappa myeloma protein.12

Use in Specific Populations

Pregnancy. There are no studies with elotuzumab in pregnant women to inform any drug-associated risks.12

Lactation. Breastfeeding is not recommended while receiving elotuzumab therapy.12

Reproductive potential. Pregnancy testing is required before starting treatment with lenalidomide in women of reproductive potential. There is a risk for fetal harm when elotuzumab is used with lenalidomide, including life-threatening birth defects.12

Pediatric use. The safety and effectiveness of elotuz­umab have not been established in pediatric patients.12

Geriatric use. Of the 646 patients in the ELOQUENT-2 trial, 57% were aged ≥65 years.12 No overall differences were observed with elotuzumab between patients aged ≥65 years or <65 years.12

Conclusion

Elotuzumab is the first immunostimulatory monoclonal antibody targeting SLAMF7 to receive FDA approval for the treatment of patients with multiple myeloma who have used previous treatments. When used with lenalidomide and dexamethasone, elotuzumab significantly enhanced PFS and response rates. Many clinical trials are under way to determine the role of elotuzumab in patients with multiple myeloma, including ELOQUENT-1, which is comparing elotuzumab plus lenalidomide and dexamethasone versus lenalidomide plus dexamethasone in patients with newly diagnosed disease, as well as studies of elotuzumab in the relapsed or refractory setting.16 Clinical trials in the latter group are assessing the combination of elotuzumab, pomalidomide, and dexamethasone; and the combination of elotuzumab with nivolumab, a PD-1 inhibitor.16

 


References

  1. National Cancer Institute. A snapshot of myeloma. November 5, 2014. www.cancer.gov/researchandfunding/snapshots/myeloma. Accessed December 15, 2015.
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): multiple myeloma. Version 3.2016. January 15, 2016. www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed December 15, 2015.
  3. American Cancer Society. Multiple myeloma: what are the key statistics about multiple myeloma? Revised January 19, 2016. www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-key-statistics. Accessed December 8, 2015.
  4. Smith L, McCourt O, Henrich M, et al. Multiple myeloma and physical activity: a scoping review. BMJ Open. 2015;5:e009576. Erratum in: BMJ Open. 2016;6:e009576corr1.
  5. Mayo Clinic staff. Diseases and conditions: multiple myeloma: treatments and drugs. December 4, 2015. www.mayoclinic.org/diseases-conditions/multiple-myelomabasics/treatment/con-20026607. Accessed December 15, 2015.
  6. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.
  7. Andrews SW, Kabrah S, May JE, et al. Multiple myeloma: the bone marrow microenvironment and its relation to treatment. Br J Biomed Sci. 2013;70:110-120.
  8. Teitelbaum A, Ba-Mancini A, Huang H, Henk HJ. Health care costs and resource utilization, including patient burden, associated with novel-agent-based treatment versus other therapies for multiple myeloma: findings using real-world claims data. Oncologist. 2013;18:37-45.
  9. Garrison LP Jr, Wang S-T, Huang H, et al. The cost-effectiveness of initial treatment of multiple myeloma in the U.S. with bortezomib plus melphalan and prednisone versus thalidomide plus melphalan and prednisone or lenalidomide plus melphalan and prednisone with continuous lenalidomide maintenance treatment. Oncologist. 2013;18:27-36.
  10. Munshi NC, Anderson KC. New strategies in the treatment of multiple myeloma. Clin Cancer Res. 2013;19:3337-3344.
  11. US Food and Drug Administration. FDA approves Empliciti, a new immune-stimulating therapy to treat multiple myeloma. Press release. November 30, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm474684.htm. Accessed December 15, 2015.
  12. Empliciti (elotuzumab) for injection [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; November 2015.
  13. Lonial S, Dimopoulos M, Palumbo A, et al; for the ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621-631.
  14. Dimopoulos MA, Lonial S, White D, et al. Eloquent-2 update: a phase 3, randomized, open-label study of elotuzumab in combination with lenalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma—3-year safety and efficacy follow-up. Blood. 2015;126. Abstract 28.
  15. Bristol-Myers Squibb. New longer-term data for Empliciti (elotuzumab) showed a continued progression-free survival benefit in patients with relapsed or refractory multiple myeloma. Press release. December 5, 2015. news.bms.com/press-release/new-longer-term-data-empliciti-elotuzumab-showed-continued-progression-free-survival-b. Accessed December 19, 2015.
  16. ClinicalTrials.gov. Elotuzumab. Search results. https://clinicaltrials.gov/ct2/results?term=Elotuzumab&Search=Search. Accessed February 16, 2016.
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Last modified: May 18, 2016