European Commission Approves Empliciti (elotuzumab) Plus Pomalidomide and Low-Dose Dexamethasone (EPd) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Median progression-free survival and overall response rate doubled among patients receiving EPd compared to pomalidomide and low-dose dexamethasone alone

Second Empliciti-based combination approved in Europe for patients with relapsed and refractory multiple myeloma

PRINCETON, N.J.–(BUSINESS WIRE)–$BMY #BMS—Bristol-Myers Squibb Company (NYSE: BMY) today announced that the European Commission (EC) has approved Empliciti (elotuzumab) plus pomalidomide and low-dose dexamethasone (EPd) for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI), and have demonstrated disease progression on the last therapy. This approval is based on data from the ELOQUENT-3 trial in which EPd doubled both median progression-free survival (PFS) and overall response rate (ORR) among patients with relapsed and refractory multiple myeloma versus pomalidomide and low-dose dexamethasone (Pd) alone.

“Multiple myeloma is a frequently recurring disease and the chance it will return after initial treatment is a heavy burden for patients to carry,” said Fouad Namouni, M.D., head, Oncology Development, Bristol-Myers Squibb. “We are proud that the European Commission has again recognized the role of Empliciti in helping European patients with multiple myeloma by approving a second Empliciti-based regimen in the relapsed and refractory setting.”

EPd is the first triplet combination approved in Europe based on a randomized clinical trial using the standard of care, Pd, as a comparator. Results from ELOQUENT-3 demonstrated that the addition of Empliciti to Pd can significantly prolong survival without disease progression among heavily pretreated patients with multiple myeloma regardless of the number of prior therapies received. Investigator-assessed PFS, the study’s primary endpoint, was 10.25 months (95% CI: 5.59 to not estimable) among patients randomized to EPd compared with 4.67 months (95% CI: 2.83 to 7.16) among patients treated with Pd alone, indicating a 46% reduction in risk of disease progression (HR 0.54; 95% CI: 0.34 to 0.86; p=0.0078) between EPd and Pd arms after a minimum follow-up of 9.1 months. A secondary endpoint of the study, ORR, was 53.3% (95% CI: 40.0 to 66.3) compared with 26.3% (95% CI: 15.5 to 39.7; p=0.0029) among patients receiving EPd or Pd, respectively.

“The approval of this elotuzumab-based triplet combination in the relapsed and refractory setting gives patients, and their doctors, a treatment alternative shown to have the potential to offer patients more time living without disease progression, coupled with a tolerable safety profile,” said Meletios A. Dimopoulos, M.D., professor and chairman of the Department of Clinical Therapeutics at National and Kapodistrian University of Athens.

Data from the ELOQUENT-3 trial were first presented at the 23^rd Congress of the European Hematology Association (EHA) in 2018. Updated efficacy results with a minimum follow-up of 18.3 months were presented at the 24^th Congress of the EHA this year. In this exploratory analysis, a total of 40 (67%) patients were alive in the EPd arm and 29 (51%) patients were alive in the Pd arm (HR 0.54; 95% CI: 0.30 to 0.96). Median OS was not reached for the EPd treatment arm.

Treatment-related Grade 3-4 adverse events (AEs) were comparable between EPd and Pd groups. Any-grade infections occurred in 65% of patients in both arms. Rates of the most commonly occurring Grade 3-4 hematologic AEs, neutropenia and anemia, were 13% and 10%, respectively, for patients receiving EPd and 27% and 20%, respectively, for patients receiving Pd, despite longer exposure within the EPd arm and similar dose intensity of pomalidomide between arms. AEs led to discontinuation in 18% of patients in the EPd arm, compared with 24% of patients in the Pd arm.

The U.S. Food and Drug Administration (FDA) approved EPd for the treatment of adult patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a PI, in November 2018.

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

About ELOQUENT-3

The Phase 2 ELOQUENT-3 trial randomized 117 patients with relapsed and refractory multiple myeloma to treatment with EPd (n=60) or Pd (n=57) in 28-day cycles until disease progression or unacceptable toxicity. In the EPd arm, Empliciti was administered intravenously at the dose of 10 mg/kg each week for the first 2 cycles and 20 mg/kg every four week thereafter. The median number of treatment cycles was nine for the EPd arm and five for the Pd arm.

Bristol-Myers Squibb: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. The focus of our research is to increase quality, long-term survival for patients and make cure a possibility. Through a unique multidisciplinary approach powered by translational science, we harness our deep scientific experience in oncology and Immuno-Oncology (I-O) research to identify novel treatments tailored to individual patient needs. Our researchers are developing a diverse, purposefully built pipeline designed to target different immune system pathways and address the complex and specific interactions between the tumor, its microenvironment and the immune system. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines, like I-O, a reality for patients.

About Empliciti

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 also is 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.

Empliciti was initially approved by the FDA in 2015 in combination with lenalidomide and dexamethasone (ELd) for the treatment of patients with multiple myeloma who have received one to three prior therapies. In 2018, Empliciti was approved by the FDA in a new combination, with pomalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a PI. The ELd and EPd indications were subsequently approved by the EC in 2016 and 2019, respectively.

U.S. FDA-APPROVED INDICATIONS FOR EMPLICITI^®

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^® (elotuzumab) 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.

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.

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%).

Please see the full Prescribing Information.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube and Facebook.

About AbbVie in Oncology

At AbbVie, we strive to discover and develop medicines that deliver transformational improvements in cancer treatment by uniquely combining our deep knowledge in core areas of biology with cutting-edge technologies, and by working together with our partners – scientists, clinical experts, industry peers, advocates, and patients. We remain focused on delivering these transformative advances in treatment across some of the most debilitating and widespread cancers. We are also committed to exploring solutions to help patients obtain access to our cancer medicines. With the acquisitions of Pharmacyclics in 2015 and Stemcentrx in 2016, our research and development efforts, and through collaborations, AbbVie’s oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 200 clinical trials and more than 20 different tumor types. For more information, please visit http://www.abbvie.com/our-science/therapeutic-focus-areas/oncology.html.

Bristol-Myers Squibb Forward-Looking Statement

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, whether Empliciti for the additional indications described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol-Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2018, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol-Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

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