Bristol-Myers Squibb Company and AbbVie announced the US Food and Drug Administration (FDA) has approved Empliciti (elotuzumab) for the treatment of multiple myeloma as combination therapy with Revlimid (lenalidomide) and dexamethasone (ERd) in patients who have received one to three prior therapies.

The approval of this first and only immunostimulatory antibody for multiple myeloma is based on data from the randomized, open-label, phase 3, ELOQUENT-2 study, which demonstrated that the ERd regimen resulted in a 30 per cent reduction in the risk of disease progression or death compared to Rd alone (HR 0.70 [95 per cent CI: 0.57, 0.85; p = 0.0004]).

The co-primary endpoints were progression-free survival (PFS), as assessed by hazard ratio, and overall response rate (ORR). With a minimum of two years follow-up, ERd delivered a benefit in PFS that was maintained over time, with PFS rates of 68 per cent versus 57 per cent at one year and 41 per cent versus 27 per cent at two years in the ERd and Rd arms, respectively. The ERd regimen also demonstrated a significant improvement in ORR, achieving an ORR of 78.5 per cent (95 per cent CI: 73.6 per cent to 82.9 per cent) versus 65.5 per cent in the Rd arm (95 per cent CI: 60.1 per cent to 70.7 per cent). The most common adverse reactions in ERd and Rd, respectively (>20 per cent) were fatigue (61.6 per cent, 51.7 per cent), diarrhea (46.9 per cent, 36.0 per cent), pyrexia (37.4 per cent, 24.6 per cent), constipation (35.5 per cent, 27.1 per cent), cough (34.3 per cent, 18.9 per cent), peripheral neuropathy (26.7 per cent, 20.8 per cent), nasopharyngitis (24.5 per cent, 19.2 per cent), upper respiratory tract infection (22.6 per cent, 17.4 per cent), decreased appetite (20.8 per cent, 12.6 per cent), and pneumonia (20.1 per cent, 14.2 per cent).

“At Bristol-Myers Squibb, we are leading a revolution in cancer treatment that is changing expectations for patients with some of the hardest-to-treat cancers. With today’s approval of Empliciti, we are pleased to now bring the promise of our Immuno-Oncology research to patients with multiple myeloma,” said Francis Cuss, MB Bchir, FRCP, chief scientific officer, Bristol-Myers Squibb.

“Empliciti represents a fundamentally different approach of directly activating the immune system in patients with relapsed or refractory multiple myeloma, delivering improved outcomes for those in need.”

Empliciti is available for injection for intravenous use in 300 mg and 400 mg vials. The company expects to begin shipping Empliciti within the next 48 hours. Empliciti is also under review by the European Medicines Agency and has been granted accelerated assessment.

Discontinuation rates due to adverse reactions were similar across the ERd and Rd control arms (6.0 per cent vs. 6.3 per cent). ERd is associated with the following Warnings and Precautions: infusion reactions, infections, second primary malignancies, hepatotoxicity, interference with determination of complete response, pregnancy/females and males of reproductive potential, and adverse reactions.

“Multiple myeloma remains largely incurable, with only half of patients surviving five years after diagnosis,” said Sagar Lonial, M.D., chief medical officer of the Winship Cancer Institute of Emory University. “The approval of elotuzumab (Empliciti) provides renewed hope for the multiple myeloma community who urgently need a treatment option that extends the time patients live without their disease progressing.”

"Empliciti in combination with lenalidomide and dexamethasone is an important new option for patients with multiple myeloma and healthcare providers who are treating this cancer," said Michael Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie.

"AbbVie is pleased to have partnered with Bristol-Myers Squibb in making this new treatment available for patients with relapsed or refractory multiple myeloma."

ELOQUENT-2 (CA204-004) is a randomized, open-label, phase 3 study evaluating Empliciti in combination with lenalidomide and dexamethasone (ERd) versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma. The trial enrolled 646 patients who had received one to three prior therapies. Patients were randomized 1:1 to receive either Empliciti 10 mg/kg in combination with Rd or Rd alone in 4-week cycles until disease progression or unacceptable toxicity. Baseline patient demographics and disease characteristics were well balanced between treatment arms and included a meaningful portion of patients who were = 65 years old, had high-risk cytogenetics, and/or were refractory to the most recent line of therapy. The minimum follow-up for all study subjects was 24 months. The co-primary endpoints were PFS, as assessed by hazard ratio, and ORR as determined by a blinded Independent Review Committee using the European Group for Blood and Marrow Transplantation response criteria. Results of the ELOQUENT-2 study were published in The New England Journal of Medicine on June 2, 2015.

The study demonstrated that the ERd regimen resulted in a 30 per cent reduction in the risk of disease progression or death compared to Rd alone (HR 0.70 [95 per cent CI: 0.57, 0.85; p = 0.0004]). Additionally, the PFS rates in the ERd arm versus the Rd arm were 68 per cent versus 57 per cent at one year and 41 per cent versus 27 per cent at two years, respectively. The ERd regimen demonstrated a significant improvement in ORR, achieving an ORR of 78.5 per cent (95 per cent CI, 73.6 per cent to 82.9 per cent; p = 0.0002) in the ERd arm versus 65.5 per cent in the Rd arm (95 per cent CI, 60.1 per cent to 70.7 per cent). The median PFS in the ERd group was 19.4 months (95 per cent CI, 16.6 to 22.2) versus 14.9 months (95 per cent CI, 12.1 to 17.2) in the Rd group. At the time of the interim analysis, there were fewer deaths in the ERd versus Rd study arm (94 [29 per cent] versus 116 [36 per cent], respectively).

Serious adverse reactions were reported in 65.4 per cent of patients treated on the ERd arm and 56.5 per cent for patients treated on the Rd arm. The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15.4 per cent, 11 per cent), pyrexia (6.9 per cent, 4.7 per cent), respiratory tract infection (3.1 per cent, 1.3 per cent), anemia (2.8 per cent, 1.9 per cent), pulmonary embolism (3.1 per cent, 2.5 per cent), and acute renal failure (2.5 per cent, 1.9 per cent). The most common adverse reactions in ERd and Rd, respectively (>20 per cent) are fatigue (61.6 per cent, 51.7 per cent), diarrhea (46.9 per cent, 36.0 per cent), pyrexia (37.4 per cent, 24.6 per cent), constipation (35.5 per cent, 27.1 per cent), cough (34.3 per cent, 18.9 per cent), peripheral neuropathy (26.7 per cent, 20.8 per cent), nasopharyngitis (24.5 per cent, 19.2 per cent), upper respiratory tract infection (22.6 per cent, 17.4 per cent), decreased appetite (20.8 per cent, 12.6 per cent), and pneumonia (20.1 per cent, 14.2 per cent). Infusion reactions occurred in 10 per cent of patients treated with ERd; these adverse events were Grade 3 or lower (Grade 3, 1 per cent; Grade 4, 0 per cent) and were manageable. In the trial, 1 per cent of patients discontinued due to infusion reactions and 5 per cent of patients required interruption of the administration of Empliciti for a median of 25 minutes. Grade 3/4 laboratory abnormalities that worsened from baseline and had a 10 per cent or higher incidence for ERd patients and a 5 per cent higher incidence than Rd patients were: lymphopenia (76.7 per cent, 48.7 per cent), leukopenia (32.4 per cent, 25.6 per cent), hyperglycemia (17.0 per cent, 10.2 per cent), and hypocalcemia (11.3 per cent and 4.7 per cent). Overall, the proportion of patients who discontinued treatment due to adverse reactions was similar for the ERd and Rd arms (6.0 per cent vs. 6.3 per cent, respectively).

“The approval of Empliciti is an innovative advancement in the treatment of multiple myeloma,” said Walter M. Capone, chief executive officer and president, The Multiple Myeloma Research Foundation. “This is an exciting opportunity for patients who experience relapse and may benefit from this new immunotherapy treatment."

Empliciti is an immunostimulatory antibody that specifically targets signaling lymphocyte activation molecule family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on Natural Killer cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.

Empliciti has a dual mechanism-of-action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity.

Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities. Prior to approval, Empliciti was granted Breakthrough Therapy Designation by the FDA for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received one to three prior therapies. According to the FDA, Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation requires preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.

Multiple myeloma is a hematologic, or blood, cancer that develops in the bone marrow. It occurs when a plasma cell, a type of cell in the soft center of bone marrow, becomes cancerous and multiplies uncontrollably. Common symptoms of multiple myeloma include bone pain, fatigue, kidney impairment, and infections.

Despite advances in multiple myeloma treatment over the last decade, less than half of patients survive for five or more years after diagnosis. A common characteristic for many patients is that they experience a cycle of remission and relapse, in which they stop treatment for a short time, but eventually return to a treatment shortly after. It is estimated that annually, more than 114,200 new cases of multiple myeloma are diagnosed and more than 80,000 people die from the disease globally.