Phase 3 trial did not meet pri­mary end­point of pro­gres­sion-free sur­vival in patients not eli­gible for trans­plant

Princeton, NJ (Press Release) – Bristol Myers Squibb Com­pany (NYSE: BMY) to­day an­nounced top­line re­­sults from ELOQUENT-1, a Phase 3, ran­dom­ized, open-label trial eval­u­ating the com­bi­na­tion of Empliciti (elo­tuzu­mab) plus Revlimid (lena­lido­mide) and dexa­meth­a­sone (ERd), versus Revlimid and dexa­meth­a­sone alone (Rd), in patients with newly diag­nosed, pre­vi­ously untreated mul­ti­ple myeloma who are trans­plant in­eli­gible. Both treat­ments were admin­istered con­tin­uously until dis­ease pro­gres­sion. At final analysis, the addi­tion of Empliciti did not show a statistically sig­nif­i­cant im­prove­ment in pro­gres­sion-free sur­vival (PFS), the study’s pri­mary end­point. The safety profile of ERd was generally con­sis­tent with the known profile of Empliciti plus Revlimid and dexa­meth­a­sone. The com­pany will com­plete a full evaluation of the ELOQUENT-1 data and work with in­ves­ti­ga­tors to present the re­­sults at a future med­i­cal meeting.

“While we are disappointed that the ELOQUENT-1 trial did not meet its pri­mary end­point in these pre­vi­ously untreated, trans­plant in­eli­gible patients, the Empliciti, Revlimid and dexa­meth­a­sone com­bi­na­tion remains a standard treat­ment for patients with re­lapsed / re­frac­tory mul­ti­ple myeloma, providing the poten­tial for im­proved sur­vival in this pop­u­la­tion of patients who are in need of addi­tional treat­ment op­tions,” said Noah Berkowitz, M.D., Ph.D., senior vice pres­i­dent, Global Clinical De­vel­op­ment, He­ma­tol­ogy, Bristol Myers Squibb.

“Multiple myeloma is an aggressive dis­ease char­ac­ter­ized by relapse and the like­li­hood to be re­frac­tory to sev­er­al ther­a­pies,” said Meletios A. Dimopoulos, M.D., pro­fessor and chairman of the ­De­part­ment of Clinical Thera­peutics at Kapodistrian Uni­ver­sity of Athens School of Medicine. “While the elotuzumab, lena­lido­mide and dexa­meth­a­sone com­bi­na­tion was unable to show a ben­e­fit in patients with newly diag­nosed mul­ti­ple myeloma at this time, it remains an im­por­tant treat­ment op­tion in the re­lapsed / re­frac­tory setting.”

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

About ELOQUENT-1

ELOQUENT-1 is a Phase 3, ran­dom­ized, open-label trial eval­u­ating Revlimid and dexa­meth­a­sone with or without Empliciti in patients with newly diag­nosed, pre­vi­ously untreated mul­ti­ple myeloma. The pur­pose of the study was to de­ter­mine whether the addi­tion of Empliciti to Revlimid and low-dose dexa­meth­a­sone would im­prove PFS, the study’s pri­mary end­point. Secondary end­points in­clude objective re­sponse rate and over­all sur­vival.

Bristol Myers Squibb: Advancing Cancer Re­search

At Bristol Myers Squibb, patients are at the center of everything we do. The goal of our cancer re­search is to in­crease quality, long-term sur­vival and make cure a possibility. We har­ness our deep scientific ex­peri­ence, cutting-edge tech­nolo­gies and discovery plat­forms to discover, de­vel­op and de­liver novel treat­ments for patients.

Building upon our trans­for­ma­tive work and legacy in he­ma­tol­ogy and Immuno-Oncology that has changed sur­vival ex­pec­ta­tions for many cancers, our re­searchers are ad­vanc­ing a deep and diverse pipe­line across mul­ti­ple modalities. In the field of im­mune cell ther­apy, this in­cludes reg­is­tra­tional CAR T-cell agents for nu­mer­ous dis­eases, and a grow­ing early-stage pipe­line that ex­pands cell and gene ther­apy targets, and tech­nolo­gies. We are devel­op­ing cancer treat­ments directed at key bio­logical path­ways using our pro­tein homeo­stasis plat­form, a re­search ca­pa­bil­i­ty that has been the basis of our approved ther­a­pies for mul­ti­ple myeloma and sev­er­al promising com­pounds in early- to mid-stage devel­op­ment. Our scientists are targeting dif­fer­en­t im­mune sys­tem path­ways to address inter­actions be­tween tumors, the microenvironment and the im­mune sys­tem to fur­ther ex­pand upon the progress we have made and help more patients respond to treat­ment. Combining these ap­proaches is key to de­livering new op­tions for the treat­ment of cancer and addressing the grow­ing issue of re­sis­tance to immuno­therapy. We source inno­va­tion in­ternally, and in col­lab­o­ration with academia, gov­ern­ment, advocacy groups and bio­technology com­pa­nies, to help make the prom­ise of trans­formational med­i­cines 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 Revlimid and dexa­meth­a­sone 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 Pomalyst/Imnovid (poma­lido­mide) and dexa­meth­a­sone (EPd), for the treat­ment of patients with mul­ti­ple myeloma who have re­ceived at least two prior ther­a­pies, in­clud­ing lena­lido­mide and a pro­te­a­some in­hib­i­tor. The ELd and EPd in­di­ca­tions were sub­se­quently approved by the Euro­pean Com­mis­sion 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.

U.S. FDA-APPROVED INDICATIONS FOR REVLIMID®

REVLIMID® (lena­lido­mide) in com­bi­na­tion with dexa­meth­a­sone (dex) is in­di­cated for the treat­ment of adult patients with mul­ti­ple myeloma (MM).

REVLIMID is in­di­cated as main­te­nance ther­apy in adult patients with MM fol­low­ing au­tol­o­gous hema­to­poietic stem cell trans­plan­ta­tion (auto-HSCT).

REVLIMID is in­di­cated for the treat­ment of adult patients with transfusion-dependent anemia due to low-or intermediate-1–risk myelo­dys­plastic syn­dromes (MDS) asso­ci­ated with a deletion 5q cytogenetic ab­nor­mal­ity with or without addi­tional cytogenetic ab­nor­mal­i­ties.

REVLIMID is in­di­cated for the treat­ment of adult patients with mantle cell lym­phoma (MCL) whose dis­ease has re­lapsed or progressed after two prior ther­a­pies, one of which in­cluded bor­tez­o­mib.

REVLIMID in com­bi­na­tion with a ritux­i­mab­ prod­uct is in­di­cated for the treat­ment of adult patients with pre­vi­ously treated follicular lym­phoma (FL).

REVLIMID in com­bi­na­tion with a ritux­i­mab­ prod­uct is in­di­cated for the treat­ment of adult patients with pre­vi­ously treated marginal zone lym­phoma (MZL).

REVLIMID is not in­di­cated and is not rec­om­mended for the treat­ment of patients with chronic lym­pho­cytic leukemia (CLL) outside of con­trolled clin­i­cal trials.

REVLIMID is only avail­able through a restricted dis­tri­bu­tion pro­gram, REVLIMID REMS®.

Important Safety In­for­ma­tion

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBO­EMBOLISM

Embryo-Fetal Toxicity

Do not use REVLIMID during pregnancy. Lena­lido­mide, a thalido­mide analogue, caused limb ab­nor­mal­i­ties in a devel­op­mental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lena­lido­mide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive poten­tial, obtain 2 neg­a­tive pregnancy tests before start­ing REVLIMID treat­ment. Females of reproductive poten­tial must use 2 forms of con­tra­cep­tion or con­tin­uously abstain from heterosexual sex during and for 4 weeks after REVLIMID treat­ment. To avoid embryo-fetal exposure to lena­lido­mide, REVLIMID is only avail­able through a restricted dis­tri­bu­tion pro­gram, the REVLIMID REMS® pro­gram.

Information about the REVLIMID REMS pro­gram is avail­able at www.celgeneriskmanagement.com or by calling the manu­fac­turer’s toll-free num­ber 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

REVLIMID can cause sig­nif­i­cant neu­tro­penia and thrombo­cyto­penia. Eighty per­cent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four per­cent of patients had to have a sec­ond dose delay/reduction. Grade 3 or 4 hema­to­logic toxicity was seen in 80% of patients en­rolled in the study. Patients on ther­apy for del 5q MDS should have their com­plete blood counts monitored weekly for the first 8 weeks of ther­apy and at least monthly there­after. Patients may re­quire dose inter­rup­tion and/or re­duc­tion. Patients may re­quire use of blood prod­uct sup­port and/or growth factors.

Venous and Arterial Thromboembolism

REVLIMID has dem­onstrated a sig­nif­i­cantly in­creased risk of deep vein thrombosis (DVT) and pul­mo­nary embolism (PE), as well as risk of myo­cardial infarction and stroke in patients with MM who were treated with REVLIMID and dexa­meth­a­sone ther­apy. Monitor for and advise patients about signs and symp­toms of thromboembolism. Advise patients to seek im­medi­ate med­i­cal care if they de­vel­op symp­toms such as short­ness of breath, chest pain, or arm or leg swelling. Thrombo­pro­phy­laxis is rec­om­mended and the choice of regi­men should be based on an assess­ment of the patient’s under­lying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when admin­istered to a pregnant female and is con­tra­in­di­cated in females who are pregnant. If this drug is used during pregnancy or if the patient be­comes pregnant while taking this drug, the patient should be apprised of the poten­tial risk to the fetus.

Severe Hypersensitivity Reactions: REVLIMID is con­tra­in­di­cated in patients who have dem­onstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syn­drome, toxic epider­mal necrolysis) to lena­lido­mide.

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS.

• Females of Reproductive Potential: See Boxed WARNINGS.
• Males: Lena­lido­mide is present in the semen of patients re­ceiv­ing the drug. Males must always use a latex or syn­thet­ic condom during any sexual contact with females of reproductive poten­tial while taking REVLIMID and for up to 4 weeks after dis­con­tin­u­ing REVLIMID, even if they have undergone a suc­cess­ful vasectomy. Male patients taking REVLIMID must not donate sperm.
• Blood Donation: Patients must not donate blood during treat­ment with REVLIMID and for 4 weeks fol­low­ing dis­con­tinu­a­tion of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID.

REVLIMID REMS® Program: See Boxed WARNINGS. Prescribers and pharmacies must be certified with the REVLIMID REMS pro­gram by en­rolling and complying with the REMS re­quire­ments; pharmacies must only dispense to patients who are authorized to re­ceive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS re­quire­ments; female patients of reproductive poten­tial who are not pregnant must comply with the pregnancy testing and con­tra­cep­tion re­quire­ments and males must comply with con­tra­cep­tion re­quire­ments.

Hematologic Toxicity: REVLIMID can cause sig­nif­i­cant neu­tro­penia and thrombo­cyto­penia. Monitor patients with neu­tro­penia for signs of in­fec­tion. Advise patients to observe for bleeding or bruising, especially with use of con­com­i­tant med­i­ca­tions that may in­crease risk of bleeding. Patients may re­quire a dose inter­rup­tion and/or dose re­duc­tion. MM: Monitor com­plete blood counts (CBC) in patients taking REVLIMID + dexa­meth­a­sone or REVLIMID as main­te­nance ther­apy, every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days there­after. MDS: Monitor CBC in patients on ther­apy for del 5q MDS, weekly for the first 8 weeks of ther­apy and at least monthly there­after. See Boxed WARNINGS for fur­ther in­for­ma­tion. MCL: Monitor CBC in patients taking REVLIMID for MCL weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly there­after. FL/MZL: Monitor CBC in patients taking REVLIMID for FL or MZL weekly for the first 3 weeks of Cycle 1 (28 days), every 2 weeks during Cycles 2-4, and then monthly there­after.

Venous and Arterial Thromboembolism: See Boxed WARNINGS. Venous thrombo­embolic events (DVT and PE) and arterial thromboses (MI and CVA) are in­creased in patients treated with REVLIMID. Patients with known risk factors, in­clud­ing prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hyper­tension, smoking). Thrombo­pro­phy­laxis is rec­om­mended and the regi­men should be based on the patient’s under­lying risks. ESAs and estrogens may fur­ther in­crease the risk of thrombosis and their use should be based on a ben­e­fit-risk de­ci­sion.

Increased Mortality in Patients With CLL: In a clin­i­cal trial in the first-line treat­ment of patients with CLL, single-agent REVLIMID ther­apy in­creased the risk of death as com­pared to single-agent chlorambucil. Serious adverse cardiovascular reac­tions, in­clud­ing atrial fibrillation, myo­cardial infarction, and cardiac failure, oc­curred more fre­quently in the REVLIMID arm. REVLIMID is not in­di­cated and not rec­om­mended for use in CLL outside of con­trolled clin­i­cal trials.

Second Primary Malig­nan­cies (SPM): In clin­i­cal trials in patients with MM re­ceiv­ing REVLIMID and in patients with FL or MZL re­ceiv­ing REVLIMID + ritux­i­mab­ ther­apy, an in­crease of hema­to­logic plus solid tumor SPM, notably AML, have been observed. In patients with MM, MDS was also observed. Monitor patients for the devel­op­ment of SPM. Take into account both the poten­tial ben­e­fit of REVLIMID and risk of SPM when con­sidering treat­ment.

Increased Mortality With Pem­bro­lizu­mab: In clin­i­cal trials in patients with MM, the addi­tion of pem­bro­lizu­mab to a thalido­mide analogue plus dexa­meth­a­sone re­­sulted in in­creased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking anti­body in com­bi­na­tion with a thalido­mide analogue plus dexa­meth­a­sone is not rec­om­mended outside of con­trolled clin­i­cal trials.

Hepatotoxicity: Hepatic failure, in­clud­ing fatal cases, has oc­curred in patients treated with REVLIMID + dexa­meth­a­sone. Pre-existing viral liver dis­ease, elevated base­line liver enzymes, and con­com­i­tant med­i­ca­tions may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to base­line values, treat­ment at a lower dose may be con­sidered.

Severe Cutaneous Reactions: Severe cu­tane­ous reac­tions in­clud­ing Stevens-Johnson syn­drome (SJS), toxic epider­mal necrolysis (TEN), and drug reac­tion with eosinophilia and sys­temic symp­toms (DRESS) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash asso­ci­ated with thalido­mide treat­ment should not re­ceive REVLIMID. Consider REVLIMID inter­rup­tion or dis­con­tinu­a­tion for Grade 2-3 skin rash. Permanently dis­con­tinue REVLIMID for Grade 4 rash, exfoliative or bullous rash, or for other severe cu­tane­ous reac­tions such as SJS, TEN, or DRESS.

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treat­ment with REVLIMID. The patients at risk of TLS are those with high tumor burden prior to treat­ment. Closely monitor patients at risk and take appro­pri­ate preventive ap­proaches.

Tumor Flare Reaction (TFR): TFR has oc­curred during inves­ti­ga­tional use of REVLIMID for CLL and lym­phoma. Monitoring and evaluation for TFR is rec­om­mended in patients with MCL, FL, or MZL. Tumor flare may mimic the pro­gres­sion of dis­ease (PD). In patients with Grade 3 or 4 TFR, it is rec­om­mended to withhold treat­ment with REVLIMID until TFR re­solves to ≤Grade 1. REVLIMID may be con­tinued in patients with Grade 1 and 2 TFR without inter­rup­tion or mod­i­fi­ca­tion, at the physician’s discretion.

Impaired Stem Cell Mobilization: A de­crease in the num­ber of CD34+ cells collected after treat­ment (>4 cycles) with REVLIMID has been reported. Consider early referral to trans­plant center to op­ti­mize timing of the stem cell collection.

Thyroid Disorders: Both hypo­thy­roid­ism and hyperthyroidism have been reported. Measure thyroid function before start­ing REVLIMID treat­ment and during ther­apy.

Early Mortality in Patients With MCL: In another MCL study, there was an in­crease in early deaths (within 20 weeks); 12.9% in the REVLIMID arm versus 7.1% in the con­trol arm. Risk factors for early deaths in­clude high tumor burden, MIPI score at diag­nosis, and high WBC at base­line (≥10 x 109/L).

Hypersensitivity: Hypersensitivity, in­clud­ing angioedema, anaphylaxis, and anaphylactic reac­tions to REVLIMID has been reported. Permanently dis­con­tinue REVLIMID for angioedema and anaphylaxis.

ADVERSE REACTIONS

Multiple Myeloma

• In newly diag­nosed: The most fre­quently reported Grade 3 or 4 reac­tions in­cluded neu­tro­penia, anemia, thrombo­cyto­penia, pneu­monia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leu­ko­penia. The highest frequency of in­fec­tions occurred in Arm Rd Continuous (75%) com­pared to Arm MPT (56%). There were more Grade 3 and 4 and serious adverse reac­tions of in­fec­tion in Arm Rd Continuous than either Arm MPT or Rd18.
• The most common adverse reac­tions reported in ≥20% (Arm Rd Continuous): diarrhea (45%), anemia (44%), neu­tro­penia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash (26%), de­creased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (20%), muscle spasms (20%), and thrombo­cyto­penia (20%).
• Maintenance Therapy Post Auto-HSCT: The most fre­quently reported Grade 3 or 4 reac­tions in ≥20% (REVLIMID arm) in­cluded neu­tro­penia, thrombo­cyto­penia, and leu­ko­penia. The serious adverse reac­tions of lung in­fec­tion and neu­tro­penia (more than 4.5%) occurred in the REVLIMID arm.
• The most fre­quently reported adverse reac­tions in ≥20% (REVLIMID arm) across both main­te­nance studies (Study 1, Study 2) were neu­tro­penia (79%, 61%), thrombo­cyto­penia (72%, 24%), leu­ko­penia (23%, 32%), anemia (21%, 9%), upper res­pira­tory tract in­fec­tion (27%, 11%), bronchitis (4%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (54%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 20%).
• After at least one prior ther­apy: The most common adverse reac­tions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neu­tro­penia (42% vs 6%), con­sti­pa­tion (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (27% vs 23%), periph­eral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper res­pira­tory tract in­fec­tion (25% vs 16%), dyspnea (24% vs 17%), dizzi­ness (23% vs 17%), thrombo­cyto­penia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight de­creased (20% vs 15%).

Myelodysplastic Syndromes

• Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neu­tro­penia (53%), thrombo­cyto­penia (50%), pneu­monia (7%), rash (7%), anemia (6%), leu­ko­penia (5%), fatigue (5%), dyspnea (5%), and back pain (5%).
• Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombo­cyto­penia (61.5%), neu­tro­penia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), con­sti­pa­tion (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), periph­eral edema (20%), cough (20%), dizzi­ness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper res­pira­tory tract in­fec­tion (15%).

Mantle Cell Lymphoma

• Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) in­cluded neu­tro­penia (43%), thrombo­cyto­penia (28%), anemia (11%), pneu­monia (9%), leu­ko­penia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neu­tro­penia (6%).
• Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial in­cluded neu­tro­penia (49%), thrombo­cyto­penia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), periph­eral edema (16%), con­sti­pa­tion (16%), and leu­ko­penia (15%).

Follicular Lymphoma/Marginal Zone Lymphoma

• Fatal adverse reac­tions occurred in 6 patients (1.5%) re­ceiv­ing REVLIMID + ritux­i­mab­ across both trials. Fatal adverse reac­tions (1 each) in­cluded: cardio-respiratory arrest, arrhythmia, car­dio­pul­mo­nary failure, multiple organ dysfunction syn­drome, sepsis, and acute kidney injury. The most fre­quent serious adverse reac­tion that occurred in the REVLIMID + ritux­i­mab­ arm was febrile neu­tro­penia (3.0%).
• Grade 3 and 4 adverse reac­tions reported in ≥5% of patients treated in the FL/MZL trial with REVLIMID + ritux­i­mab­ were: neu­tro­penia (50%) and leu­ko­penia (7%).
• Adverse reac­tions reported in ≥15% of patients with FL/MZL treated with REVLIMID + ritux­i­mab­ were: neu­tro­penia (58%), diarrhea (31%), con­sti­pa­tion (26%), cough (24%), fatigue (22%), rash (22%), pyrexia (21%), leu­ko­penia (20%), pruritus (20%), upper res­pira­tory tract in­fec­tions (18%), abdominal pain (18%), anemia (16%), headache (15%), thrombo­cyto­penia (15%).

DRUG INTERACTIONS

Periodically monitor digoxin plasma levels due to in­creased Cmax and AUC with con­com­i­tant REVLIMID ther­apy. Patients taking con­com­i­tant ther­a­pies such as erythropoietin-stimulating agents or estrogen-containing ther­a­pies may have an in­creased risk of thrombosis. It is not known whether there is an inter­action be­tween dexa­meth­a­sone and warfarin. Close monitoring of PT and INR is rec­om­mended in patients with MM taking con­com­i­tant warfarin.

USE IN SPECIFIC POPULATIONS

• Pregnancy: See Boxed WARNINGS: If pregnancy does occur during treat­ment, im­medi­ately dis­con­tinue the drug and refer patient to an obstetrician/gynecologist ex­peri­enced in reproductive toxicity for further evaluation and counseling. There is a REVLIMID pregnancy exposure registry that monitors pregnancy out­comes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to under­stand the root cause for the pregnancy. Report any sus­pected fetal exposure to REVLIMID to the FDA via the MedWatch pro­gram at 1-800-FDA-1088 and also to Celgene Corpo­ra­tion at 1-888-423-5436.
• Lactation: There is no in­for­ma­tion re­gard­ing the presence of lena­lido­mide in human milk, the effects of REVLIMID on the breastfed infant, or the effects of REVLIMID on milk pro­duc­tion. Because many drugs are excreted in human milk and because of the poten­tial for adverse reac­tions in breastfed infants from REVLIMID, advise female patients not to breastfeed during treat­ment with REVLIMID.
• Renal Impairment: Adjust the starting dose of REVLIMID based on the creatinine clear­ance value and for patients on dialysis.

Please see full Prescribing In­for­ma­tion, in­clud­ing Boxed WARNINGS, for REVLIMID.

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, Face­book and Insta­gram.

Celgene and Juno Thera­peutics are wholly owned sub­sid­i­aries of Bristol Myers Squibb Com­pany. In cer­tain countries outside the U.S., due to local laws, Celgene and Juno Thera­peutics are referred to as, Celgene, a Bristol Myers Squibb com­pany and Juno Thera­peutics, a Bristol Myers Squibb com­pany.

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 https://www.abbvie.com/our-science/therapeutic-focus-areas/oncology.html.

Cautionary State­ment Regarding Forward-Looking State­ments

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, the possibility of un­fa­vor­able re­­sults from fur­ther clin­i­cal trials involving Empliciti-based com­bi­na­tions. 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, 2019, 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.

Source: Bristol-Myers Squib.