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  • CLASSES

    Monoclonal Antibodies that Target Signaling Lymphocytic Activation Moleculr Family 7 (SLAMF7)

    DEA CLASS

    Rx

    DESCRIPTION

    Anti-SLAMF7 monoclonal antibody
    Used for multiple myeloma in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone in adult patients who have received prior therapy
    Severe and fatal infection has been reported; monitor patients and treat infection promptly

    COMMON BRAND NAMES

    Empliciti

    HOW SUPPLIED

    Empliciti Intravenous Inj Pwd F/Sol: 300mg, 400mg

    DOSAGE & INDICATIONS

    For the treatment of multiple myeloma.
    NOTE: The FDA has designated elotuzumab as an orphan drug for the treatment of multiple myeloma.
    For the treatment of multiple myeloma in patients who have received 1 to 3 prior therapies, in combination with lenalidomide and dexamethasone.
    Intravenous dosage
    Adults

    10 mg/kg IV once weekly on cycles 1 and 2 (on days 1, 8, 15, and 22), then every 2 weeks (on days 1 and 15) thereafter. Administer in combination with lenalidomide 25 mg orally daily on days 1 through 21 and dexamethasone 28 mg orally (taken 3 to 24 hours prior to elotuzumab) on days 1, 8, 15, and 22 on cycles 1 and 2 and on days 1 and 15 of subsequent cycles; give dexamethasone 40 mg orally on days 8 and 22 of cycles 3 and beyond. Repeat treatment cycles every 28 days until disease progression. Hold elotuzumab if a grade 2 or higher infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 45 to 90 minutes prior to each elotuzumab infusion: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg PO or IV (or equivalent), ranitidine 50 mg IV or 150 mg PO (or equivalent), and dexamethasone 8 mg IV. At a median follow-up time of 24.5 months, the median progression-free survival time was significantly improved with elotuzumab plus lenalidomide and dexamethasone (median duration of therapy, 17 months) compared with lenalidomide and dexamethasone alone (19.4 months vs. 14.9 months; hazard ratio (HR) = 0.7; 95% CI, 0.57 to 0.85; p less than 0.001) in patients with relapsed and/or refractory multiple myeloma in a planned interim analysis of a multicenter, randomized, open-label, phase 3 trial (n = 646; the ELOQUENT-2 trial). In this study, patients had received a median of 2 prior therapies (range, 1 to 4 therapies); 35% of patients had refractory disease to the last therapy and 54% of patients had previously received an autologous stem cell transplantation. The overall survival time was improved in the elotuzumab-containing arm (48.3 months vs. 39.6 months; HR = 0.82; 95% CI, 0.68 to 1) at the final analysis (minimum follow-up time of 70.6 months).

    For the treatment of multiple myeloma in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor, in combination with pomalidomide and dexamethasone.
    Intravenous dosage
    Adults

    10 mg/kg IV once weekly on cycles 1 and 2 (on days 1, 8, 15, and 22), then give 20 mg/kg IV every 4 weeks (on day 1) starting on cycle 3. Administer elotuzumab in combination with pomalidomide 4 mg orally daily on days 1 through 21 and oral dexamethasone (age 75 years or less, 28 mg; age over 75 years, 8 mg) at 3 to 24 hours prior to elotuzumab on days 1, 8, 15, and 22 on cycles 1 and 2 and on day 1 of subsequent cycles. Additionally, give oral dexamethasone (age 75 years or less, 40 mg; age over 75 years, 20 mg) at 3 to 24 hours prior to elotuzumab on days 8, 15, and 22 of cycles 3 and beyond. Repeat treatment cycles every 28 days until disease progression. Hold elotuzumab if a grade 2 or higher infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 45 to 90 minutes prior to each elotuzumab infusion: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg PO or IV (or equivalent), ranitidine 50 mg IV or 150 mg PO (or equivalent), and dexamethasone 8 mg IV. At a minimum follow-up time of 9.1 months, the median investigator-assessed progression-free survival time was significantly improved with elotuzumab plus pomalidomide and dexamethasone (median number of treatment cycles, 9) compared with pomalidomide and dexamethasone alone (10.25 months vs. 4.67 months; hazard ratio (HR) = 0.54; 95% CI, 0.34 to 0.86; p = 0.0078) in patients with relapsed or refractory multiple myeloma in a randomized, phase 2 trial (n = 117; the ELOQUENT-3 trial). In this study, patients had received a median of 3 prior therapies; 70% of patients had refractory disease after both lenalidomide and a proteasome inhibitor and 55% of patients had previously received an autologous stem cell transplantation.[60354]

    MAXIMUM DOSAGE

    Adults

    20 mg/kg IV.

    Geriatric

    20 mg/kg IV.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No elotuzumab dosage adjustment is necessary in patients with mild hepatic impairment based on data from a pharmacokinetic population analysis. Elotuzumab has not been studied in patients with moderate (total bilirubin level greater than 1.5- to 3-times the upper limit of normal (ULN) and any AST level) or severe (total bilirubin level greater than 3-times the ULN and any AST level) hepatic impairment. Hold elotuzumab in patients who develop grade 3 or higher elevated hepatic enzymes during therapy. Consider restarting elotuzumab therapy when hepatic enzymes return to baseline values.

    Renal Impairment

    No elotuzumab dosage adjustment is necessary in patients with renal impairment (creatinine clearance (CrCl) of 15 to 89 mL/min) or end-stage renal disease (CrCl less than 15 mL/min) with or without hemodialysis based on data from a pharmacokinetic population analysis.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Premedication with acetaminophen PO, an H1-blocker PO or IV (e.g., diphenhydramine), an H2-blocker PO or IV (e.g., ranitidine), and dexamethasone IV is required prior to each infusion; hold therapy for grade 2 or higher infusion-related reactions.
    Do not mix with other drugs or infuse with other drugs through the same IV line.
    Reconstitution:
    Calculate the appropriate dose and reconstitute (using an 18-gauge or smaller needle) the 300-mg vial with 13 mL of Sterile Water for injection and the 400-mg vial with 17 mL of Sterile Water for injection.
    Following reconstitution, each vial contains overfill to allow for a maximum withdrawal of 12 mL for the 300-mg vial and 16 mL for the 400-mg vial; the final vial concentration is 25 mg/mL.
    Swirl the solution by rotating the vial; invert the vial a few times to dissolve the powder. Do NOT agitate or shake to reconstitute.
    The lyophilized powder should dissolve within 10 minutes; allow the reconstituted solution to stand for 5 to 10 minutes after all powder is dissolved.
    Dilution:
    Withdraw the appropriate amount (mL) from the elotuzumab 25 mg/mL vials for the calculated dose; do not exceed a maximum withdrawal of 12 mL for the 300-mg vial and of 16 mL for the 400-mg vial; discard any unused portion left in the vial.
    Add the calculated amount of elotuzumab to an infusion bag made of polyvinyl chloride or polyolefin and then add enough 0.9% Sodium Chloride for injection or 5% Dextrose injection so that the final diluted admixture concentration is between 1 and 6 mg/mL.
    Do NOT exceed 5 mL/kg of patient weight at any given dose.
    Storage following dilution: The diluted admixture may be stored for up to 24 hours when refrigerated (2 to 8 degrees C or 36 to 46 degrees F) and protected from light; a maximum of 8 hours (of the total 24 hours) may be at room temperature (20 to 25 degrees C or 68 to 77 degrees F).
     
    Intravenous Infusion:
    Administer the diluted admixture using an infusion-set and a sterile, non-pyrogenic, low protein-binding filter (pore size of 0.2 to 1.2 micrometer); use an automated infusion pump.
    For the 10 mg/kg dose, administer the diluted infusion intravenously at the appropriate infusion rate as follows: Cycle 1, dose 1: start at 0.5 mL/minute for 30 minutes, increase to 1 mL/minute for 30 minutes, then increase to a maximum rate of 2 mL/minute. Cycle 1, dose 2: start at 3 mL/minute for 30 minutes, then increase to a maximum rate of 4 mL/minute. Cycle 1, doses 3 and 4, and all subsequent cycles: 5 mL/minute; do not exceed this rate.
    For the 20 mg/kg dose, administer the diluted infusion intravenously at the appropriate infusion rate as follows:Dose 1: start at 3 mL/minute for 30 minutes, then increase to a maximum rate of 4 mL/minute.Dose 2 and all subsequent doses: 5 mL/minute; do not exceed this rate.
    Up-titration of the infusion rate may be considered only in the absence of infusion reactions.
    Complete the infusion within 24 hours from reconstitution.[60354]

    STORAGE

    Empliciti:
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Infusion-related reactions

    Infusion-related reactions (e.g., chest discomfort, fever, chills, hypertension or hypotension, and bradycardia) have been reported with elotuzumab therapy; most infusion-related reactions occurred with the first infusion. Observe patients during the elotuzumab infusion for signs and symptoms of infusion-related reactions; monitor vital signs every 30 minutes for 2 hours after the end of the infusion in patients who develop a reaction. Hold therapy and initiate appropriate medical support if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Premedication with acetaminophen PO, an H1-blocker PO or IV (e.g., diphenhydramine), an H2-blocker PO or IV (e.g., ranitidine), and dexamethasone IV is required prior to each infusion. All patients should receive an additional oral dose of dexamethasone within 3 to 24 hours prior to every infusion. If dexamethasone is delayed or discontinued, consider the risk of a reaction versus the benefit of therapy when determining if a dose of elotuzumab should be administered.[60354]

    Infection

    Infection (e.g., opportunistic, fungal, and viral infections) has been reported with elotuzumab therapy; some cases resulted in death. Monitor patients for signs and symptoms of infections; treat promptly if an infection develops.

    New primary malignancy

    New primary malignancy (e.g., solid tumors, hematologic malignancies, skin cancer) has been reported with elotuzumab therapy. Monitor patients for signs and symptoms of new primary malignancies.

    Hepatic disease, hepatotoxicity

    Hepatotoxicity (e.g., elevated hepatic enzymes) has been reported with elotuzumab use. Monitor liver function tests periodically. Hold elotuzumab in patients who develop grade 3 or higher elevated hepatic enzymes during therapy. Consider restarting elotuzumab therapy when hepatic enzymes return to baseline values. No initial elotuzumab dosage adjustment appears necessary in patients with mild hepatic impairment. Use elotuzumab with caution in patients with moderate or severe hepatic disease; elotuzumab has not been studied in this patient population.

    Laboratory test interference

    Elotuzumab can be detected on both the serum protein electrophoresis (SPEP) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This laboratory test interference may affect the determination of complete response or disease progression in some patients with IgG kappa myeloma protein. Especially in patients with an endogenous myeloma protein of IgA, IgM, IgD, or lambda light chain restricted, elotuzumab may cause a small peak in the early gamma region on SPEP that is IgG kappa on IFE.

    Pregnancy

    The risk of fetal harm with elotuzumab use during pregnancy is unknown; elotuzumab has not been evaluated in pregnant women or in animal reproduction studies. Elotuzumab is given as part of a 3-drug combination regimen with lenalidomide and dexamethasone or pomalidomide and dexamethasone for the treatment of multiple myeloma; lenalidomide and pomalidomide may result in embryo-fetal harm and are contraindicated for use in pregnancy.[60354]

    Breast-feeding

    According to the manufacturer, breast-feeding is not recommended in women who are taking the 3-drug combination regimen of elotuzumab, lenalidomide, and dexamethasone or elotuzumab, pomalidomide, and dexamethasone due to a potential for serious adverse reactions in breast-fed infants. It is not known if elotuzumab is secreted in human milk or if it affects the breast-fed infant or milk production.[60354]

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 8.0-77.0
    leukopenia / Delayed / 32.0-52.0
    infection / Delayed / 13.0-28.0
    thrombocytopenia / Delayed / 17.0-19.0
    hyperglycemia / Delayed / 3.3-17.0
    asthenia / Delayed / 0-13.0
    fatigue / Early / 0-13.0
    hypocalcemia / Delayed / 3.3-11.0
    new primary malignancy / Delayed / 0-9.0
    hyperkalemia / Delayed / 5.0-7.0
    cataracts / Delayed / 0-6.0
    diarrhea / Early / 0-5.0
    hyponatremia / Delayed / 0-5.0
    hypoalbuminemia / Delayed / 1.7-3.9
    peripheral neuropathy / Delayed / 0-3.8
    dyspnea / Early / 0-3.3
    bone pain / Delayed / 0-3.3
    pulmonary embolism / Delayed / 0-3.1
    anemia / Delayed / 0-2.8
    hepatotoxicity / Delayed / 0-2.5
    fever / Early / 0-2.5
    renal failure (unspecified) / Delayed / 0-2.5
    constipation / Delayed / 1.3-1.7
    anorexia / Delayed / 0-1.6
    weight loss / Delayed / 0-1.3
    metabolic acidosis / Delayed / 0-0.4
    vomiting / Early / 0-0.3
    cough / Delayed / 0-0.3
    headache / Early / 0-0.3
    bradycardia / Rapid / Incidence not known

    Moderate

    antibody formation / Delayed / 18.5-36.0
    peripheral edema / Delayed / 0-13.0
    infusion-related reactions / Rapid / 3.3-10.0
    chest pain (unspecified) / Early / 5.0
    elevated hepatic enzymes / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    hypertension / Early / Incidence not known

    Mild

    pharyngitis / Delayed / 25.0-25.0
    muscle cramps / Delayed / 0-13.0
    hypoesthesia / Delayed / 5.0
    night sweats / Early / 5.0
    influenza / Delayed / Incidence not known
    chills / Rapid / Incidence not known

    DRUG INTERACTIONS

    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    The risk of fetal harm with elotuzumab use during pregnancy is unknown; elotuzumab has not been evaluated in pregnant women or in animal reproduction studies. Elotuzumab is given as part of a 3-drug combination regimen with lenalidomide and dexamethasone or pomalidomide and dexamethasone for the treatment of multiple myeloma; lenalidomide and pomalidomide may result in embryo-fetal harm and are contraindicated for use in pregnancy.[60354]

    According to the manufacturer, breast-feeding is not recommended in women who are taking the 3-drug combination regimen of elotuzumab, lenalidomide, and dexamethasone or elotuzumab, pomalidomide, and dexamethasone due to a potential for serious adverse reactions in breast-fed infants. It is not known if elotuzumab is secreted in human milk or if it affects the breast-fed infant or milk production.[60354]

    MECHANISM OF ACTION

    Elotuzumab is a humanized IgG1 monoclonal antibody that binds to the Signaling Lymphocytic Activation Molecule family member 7 (SLAMF7), a cell surface glycoprotein receptor, and activates natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity of SLAMF7-expressing myeloma cells. SLAMF7 is highly expressed in multiple myeloma cells and is also expressed in mature NK cells. It appears that elotuzumab does not induce complement-dependent cytotoxicity. In preclinical models, synergistic cytotoxic effects in multiple myeloma cell lines and enhanced NK cell activation have been observed with the combination of elotuzumab and lenalidomide.

    PHARMACOKINETICS

    Elotuzumab is administered as an IV infusion. The pharmacokinetic (PK) parameters of elotuzumab were evaluated in 35 adult patients with previously treated advanced multiple myeloma in a phase I dose escalation study. In 4 patients that received elotuzumab 10 mg/kg, the mean Vd was 2.98 +/- 0.37 L, the mean clearance was 15.3 +/- 8.6 mL/hour, and the mean half-life was 4.6 +/- 0.1 days following the first dose.[60364] Based on a population PK models, about 97% of the maximum steady-state elotuzumab concentration is predicted to be eliminated at a geometric mean of 82.4 days (coefficient of variance (CV), 48%) when elotuzumab is administered in combination with lenalidomide and dexamethasone and at a geometric mean of 78 days (CV, 42%) when elotuzumab is administered in combination with pomalidomide and dexamethasone. When given in combination with lenalidomide and dexamethasone, elotuzumab clearance decreased from a geometric mean of 17.5 mL/day/kg (CV, 21.2%) to 5.8 mL/day/kg (CV, 31%) with increasing doses from 0.5 mg/kg to 20 mg/kg.[60354]

    Intravenous Route

    Following the fourth dose of elotuzumab 10 mg/kg IV given every 2 weeks, the Cmax of 216.6 +/- 37.2 micrograms (mcg)/mL was achieved at a Tmax of 4.8 +/- 1.4 hours in a phase I dose escalation study in patients with advanced multiple myeloma; additionally, the AUCinf value was 27,220 mcg X hour/mL. Elotuzumab exhibits nonlinear pharmacokinetics (PK) demonstrated by greater than proportional increases in AUC values.[60364] Based on population PK models, the geometric mean steady-state trough concentration is about 194 mcg/mL (CV, 52%) when elotuzumab is administered in combination with lenalidomide and dexamethasone and about 124 mcg/mL (CV, 59%) when elotuzumab is administered in combination with pomalidomide and dexamethasone.[60354]