FDA Approves Empliciti (elotuzumab) Plus Pomalidomide and Dexamethasone, a New Immunotherapy Combination for Certain Patients with Relapsed or Refractory Multiple Myeloma

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) approved Empliciti (elotuzumab) injection for intravenous use in combination with 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.1 In ELOQUENT-3, a randomized, open-label, Phase 2 trial, 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).1

“Empliciti plus pomalidomide and dexamethasone has been proven to extend the time that certain patients live without disease progression, giving health care professionals an effective new tool to tackle this relentless cancer,”1,2 said Joseph E. Eid, M.D., senior vice president and head of Medical, Bristol-Myers Squibb. “Today’s approval reinforces the importance of Immuno-Oncology in blood cancers and expands the role of Empliciti to address the needs of relapsed or refractory multiple myeloma patients.”

Empliciti with pomalidomide and dexamethasone is associated with Warnings and Precautions related to: infusion reactions, infections, secondary primary malignancies, hepatotoxicity, interference with determination of complete response, pregnancy/females and males of reproductive potential and adverse reactions.1

Following priority review by the FDA, EPd is the first triplet combination to be approved based on a randomized clinical trial using Pd as a comparator.3,4 Results from the trial include:

• Progression-free survival (primary endpoint, investigator-assessed): 1,3 EPd reduced the risk of disease progression by 46% (hazard ratio [HR]: 0.54; 95% confidence interval [CI]: 0.34 to 0.86, p=0.0078), demonstrating a median PFS of 10.25 months (95% CI: 5.59 to non-estimable [NE]) vs. 4.67 months (95% CI: 2.83 to 7.16) for Pd alone after a minimum follow-up of 9.1 months.1
• Overall response rate (secondary endpoint, investigator-assessed): 1,3 Response rates doubled in patients receiving EPd (53.3%; n=32/60 [95% CI: 40.0 to 66.3]) compared with patients receiving Pd alone (26.3%; n=15/57 [95% CI: 15.5 to 39.7]; p=0.0029), with very good partial responses or better seen in 20% of EPd-treated patients (n=12) and 8.8% of Pd-treated patients (n=5).1
• Safety: Serious adverse reactions were reported in 22% of patients treated with EPd and in 15% of patients treated with Pd.1 Discontinuation of any component of the treatment regimen due to adverse reactions occurred in 5.0% of patients in the EPd arm, compared to 1.8% of patients in the control arm.1

“Despite remarkable recent innovations with novel therapies for the treatment of multiple myeloma, many patients still face poor outcomes, and particularly in the relapsed and relapsed, refractory setting,”5 said Paul Richardson, M.D., clinical program leader and director of clinical research of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. “This new regimen of elotuzumab combined with pomalidomide and dexamethasone not only extended the time to disease progression versus a standard of care but also doubled the response rate in some patients whose prior treatments had failed them.1,6 Thus to be able to offer an alternative with a meaningful clinical benefit is an important and significant milestone for our patients.”1,4

Approximately 31,000 people in the United States will be diagnosed with multiple myeloma this year.7 A common characteristic for many patients is that they experience multiple relapses, which means that the cancer returns after a period of remission.8,9

“Relapse can be overwhelming and extremely challenging for multiple myeloma patients, particularly after they have already tried several therapies,”10 said Paul Giusti, president and chief executive officer of the Multiple Myeloma Research Foundation. “Empliciti, in combination with pomalidomide and dexamethasone, is an exciting new option for patients with relapsed or refractory myeloma.”

Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities.

The primary efficacy outcome measure of the trial was PFS as determined by the investigator.1,3 The secondary efficacy outcome measure of ORR included complete, stringent-complete, very good partial and partial response rates as determined by investigator assessment, based on the International Myeloma Working Group criteria.1,3 Data from the ELOQUENT-3 trial were presented at the 23rd Congress of the European Hematology Association in June 2018.4

Select Safety Profile for the ELOQUENT-3 Trial

The most frequent serious adverse reactions in the population evaluated for safety (n=60 in the EPd arm and n=55 in the Pd arm) were pneumonia (13% vs. 11%) and respiratory tract infection (7% vs. 3.6%).1Infusion reactions were reported in 3.3% of patients treated with EPd.1 Adverse reactions that occurred with a >/=10% incidence for Empliciti plus pomalidomide and dexamethasone-treated patients and >/=5% incidence than pomalidomide and dexamethasone-treated patients were constipation (22% vs. 11%), hyperglycemia (20% vs. 15%), pneumonia (18% vs. 13%), diarrhea (18% vs. 9%), respiratory tract infection (17% vs. 9%), bone pain (15% vs. 9%), dyspnea (15% vs. 7%), muscle spasms (13% vs. 5%), edema peripheral (13% vs. 7%) and lymphopenia (10% vs. 1.8%).1

INDICATIONS

EMPLICITI® (elotuzumab) is indicated in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one to three prior therapies.

EMPLICITI is indicated in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

EMPLICITI is available for injection for intravenous use in 300 mg and 400 mg vials.

IMPORTANT SAFETY INFORMATION

Infusion Reactions

• Infusion reactions were reported in 10% of patients treated with EMPLICITI in the ELOQUENT-2 trial [EMPLICITI + lenalidomide + dexamethasone (ERd) vs lenalidomide + dexamethasone (Rd)] and 3.3% in the ELOQUENT-3 trial [EMPLICITI + pomalidomide + dexamethasone (EPd) vs pomalidomide + dexamethasone (Pd)].
• In the ELOQUENT-2 trial, all infusion reactions were Grade 3 or lower, with Grade 3 infusion reactions occurring in 1% of patients. The most common symptoms included fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose.
• In the ELOQUENT-3 trial, the only infusion reaction symptom was chest discomfort (2%), which was Grade 1. All the patients who experienced an infusion reaction had them during the first treatment cycle.
• If a Grade 2 or higher infusion reaction occurs, interrupt the EMPLICITI infusion and institute appropriate medical and supportive measures. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart it on that day. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment.
• Premedicate with dexamethasone, H1 blocker, H2 blocker, and acetaminophen prior to EMPLICITI infusion.

About ELOQUENT-3

ELOQUENT-3 was a randomized, open-label Phase 2 study evaluating the addition of Empliciti to pomalidomide and dexamethasone versus pomalidomide and dexamethasone in 117 patients with multiple myeloma who received two or more prior therapies and were either refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor.1,3,4 Patients were randomized 1:1 to receive either EPd (n=60) or Pd (n=57) in 28-day cycles until disease progression or unacceptable toxicity.1 The approved dose of Empliciti, when used in combination with pomalidomide and dexamethasone, is 10 mg/kg administered intravenously every week for the first two 28-day cycles, followed by 20 mg/kg every four weeks until disease progression or unacceptable toxicity.1

Infections

• In the ELOQUENT-2 trial (N=635), infections were reported in 81% of patients in the ERd arm and 74% in the Rd arm. Grade 3-4 infections were 28% (ERd) and 24% (Rd). Discontinuations due to infections were 3.5% (ERd) and 4.1% (Rd). Fatal infections were 2.5% (ERd) and 2.2% (Rd). Opportunistic infections were reported in 22% (ERd) and 13% (Rd). Fungal infections were 10% (ERd) and 5% (Rd). Herpes zoster was 14% (ERd) and 7% (Rd).
• In the ELOQUENT-3 trial (N=115), infections were reported in 65% of patients in both the EPd arm and the Pd arm. Grade 3-4 infections were reported in 13% (EPd) and 22% (Pd). Discontinuations due to infections were 7% (EPd) and 5% (Pd). Fatal infections were 5% (EPd) and 3.6% (Pd). Opportunistic infections were reported in 10% (EPd) and 9% (Pd). Herpes zoster was reported in 5% (EPd) and 1.8% (Pd).
• Monitor patients for development of infections and treat promptly.

Second Primary Malignancies

• In the ELOQUENT-2 trial (N=635), invasive second primary malignancies (SPM) were 9% (ERd) and 6% (Rd). The rate of hematologic malignancies was the same between ERd and Rd treatment arms (1.6%). Solid tumors were reported in 3.5% (ERd) and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd).
• In the ELOQUENT-3 trial (N=115), invasive SPMs were 0% (EPd) and 1.8% (Pd).
• Monitor patients for the development of SPMs.

Hepatotoxicity

• In the ELOQUENT-2 trial (N=635), AST/ALT >3X the upper limit, total bilirubin >2X the upper limit, and alkaline phosphatase <2X the upper limit were 2.5% (ERd) vs 0.6% (Rd). Of 8 patients experiencing hepatotoxicity, 2 patients discontinued treatment while 6 patients had resolution and continued. Monitor liver enzymes periodically. Stop EMPLICITI upon ≥Grade 3 elevation of liver enzymes. Continuation of treatment may be considered after return to baseline values.

Interference with Determination of Complete Response

• EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.

Pregnancy/Females and Males of Reproductive Potential

• There are no available data on EMPLICITI use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage.
• There is a risk of fetal harm, including severe life-threatening human birth defects, associated with lenalidomide and pomalidomide, and they are contraindicated for use in pregnancy. Refer to the respective product full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information.

Adverse Reactions

ELOQUENT-2 trial:

• Serious adverse reactions were 65% (ERd) and 57% (Rd). The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15%, 11%), pyrexia (7%, 5%), respiratory tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%).
• The most common adverse reactions in ERd and Rd, respectively (≥20%) were fatigue (62%, 52%), diarrhea (47%, 36%), pyrexia (37%, 25%), constipation (36%, 27%), cough (34%, 19%), peripheral neuropathy (27%, 21%), nasopharyngitis (25%, 19%), upper respiratory tract infection (23%, 17%), decreased appetite (21%, 13%), and pneumonia (20%, 14%).

ELOQUENT-3 trial:

• Serious adverse reactions were 22% (EPd) and 15% (Pd). The most frequent serious adverse reactions in the EPd arm compared to the Pd arm were: pneumonia (13%, 11%) and respiratory tract infection (7%, 3.6%).
• The most common adverse reactions in EPd arm (≥20% EPd) and Pd, respectively, were constipation (22%, 11%) and hyperglycemia (20%, 15%).