Elotuzumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Empliciti: 300 mg (1 ea) [contains polysorbate 80]

Solution Reconstituted, Intravenous [preservative free]:

Empliciti: 400 mg (1 ea) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Elotuzumab is a humanized IgG1 immunostimulatory monoclonal antibody directed against signaling lymphocytic activation molecule family member 7 (SLAMF7, also called CS1 [cell surface glycoprotein CD2 subset 1). SLAMF7 is expressed on most myeloma and natural killer cells, but not on normal tissues; more than 95% of bone marrow myeloma cells express SLAMF7 (Lonial 2015). Elotuzumab directly activates natural killer cells through both the SLAMF7 pathway and Fc receptors. It also targets SLAMF7 on myeloma cells and mediates antibody-dependent cellular cytotoxicity (ADCC) through the CD16 pathway (Lonial 2015). This immunostimulatory activity, through the increased activation of natural killer cells, increases anti-tumor activity.

Pharmacokinetics/Pharmacodynamics

Half-Life Elimination

~97% of the maximum steady-state concentration is expected to be eliminated with a geometric mean (CV%) of 78 to 82.4 days.

Use in Specific Populations

Special Populations Note

Body weight: Clearance increases with increasing body weight.

Use: Labeled Indications

Multiple myeloma, relapsed/refractory: Treatment of multiple myeloma (in combination with lenalidomide and dexamethasone) in patients who have received 1 to 3 prior therapies; treatment of multiple myeloma (in combination with pomalidomide and dexamethasone) in patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to elotuzumab or any component of the formulation.

Dosage and Administration

Dosing: Adult

Note: Premedicate with dexamethasone, an H₁-blocker (eg, diphenhydramine), an H₂-blocker (eg, ranitidine), and acetaminophen ~45 to 90 minutes prior to infusion (see Premedications below). Refer to the lenalidomide, pomalidomide, and dexamethasone monographs for dosing information.

Multiple myeloma, relapsed/refractory: IV: Continue until disease progression or unacceptable toxicity (Lonial 2015)

In combination with lenalidomide and dexamethasone (Lonial 2015):

Cycles 1 and 2: 10 mg/kg once weekly on days 1, 8, 15, and 22 of a 28-day treatment cycle (in combination with lenalidomide and dexamethasone)

Cycle 3 and beyond: 10 mg/kg once every 2 weeks on days 1 and 15 of a 28-day treatment cycle (in combination with lenalidomide and dexamethasone)

In combination with pomalidomide and dexamethasone (Dimopoulos 2018):

Cycles 1 and 2: 10 mg/kg once weekly on days 1, 8, 15, and 22 of a 28-day treatment cycle (in combination with pomalidomide and dexamethasone)

Cycle 3 and beyond: 20 mg/kg once every 4 weeks on day 1 of a 28-day treatment cycle (in combination with pomalidomide and dexamethasone)

Premedications:

Dexamethasone: Oral and IV: Note: Dexamethasone dosing differs depending on chemotherapy regimen.

Elotuzumab/lenalidomide/dexamethasone regimen:

On days that elotuzumab is administered, give dexamethasone 28 mg orally 3 to 24 hours before elotuzumab infusion plus dexamethasone 8 mg IV 45 to 90 minutes prior to infusion. On days that elotuzumab is not administered but dexamethasone is due (eg, days 8 and 22 of cycle 3 and beyond), administer the standard dexamethasone dose (40 mg orally).

Due to compliance concerns on days that elotuzumab is administered, a one-time dexamethasone dose of 20 to 40 mg IV has been reported (in lieu of administering both oral and IV dexamethasone) (Hofmeister 2016).

Elotuzumab/pomalidomide/dexamethasone regimen:

Patients ≤75 years: On days that elotuzumab is administered, give dexamethasone 28 mg orally 3 to 24 hours before elotuzumab infusion plus dexamethasone 8 mg IV 45 to 90 minutes prior to infusion. On days that elotuzumab is not administered but dexamethasone is due (eg, days 8, 15, and 22 of cycle 3 and beyond), administer dexamethasone 40 mg orally.

Patients >75 years: On days that elotuzumab is administered, give dexamethasone 8 mg orally 3 to 24 hours before elotuzumab infusion plus dexamethasone 8 mg IV 45 to 90 minutes prior to infusion. On days that elotuzumab is not administered but dexamethasone is due (eg, days 8, 15, and 22 of cycle 3 and beyond), administer dexamethasone 20 mg orally.

Antipyretic: Oral: Acetaminophen 650 to 1,000 mg

H₁-blocker: IV or Oral: Diphenhydramine 25 to 50 mg or equivalent

H₂-blocker: Ranitidine: 50 mg IV or 150 mg orally or equivalent. The use of famotidine 20 mg IV has also been reported (Hofmeister 2016).

Dosing: Geriatric

Refer to adult dosing. Concomitant therapy (eg, dexamethasone) dose may be lower in patients >75 years.

Dosing: Adjustment for Toxicity

Refer to lenalidomide and pomalidomide monographs for dosage modifications for toxicity. If dosing of one drug in the regimen is delayed, interrupted, or discontinued, treatment with the other medications may continue as scheduled. However, if dexamethasone is delayed or discontinued, administer elotuzumab based on clinical judgment (due to hypersensitivity risk).

Infusion reactions: Grade 2 or greater: Interrupt infusion and manage symptoms as clinically appropriate. When symptoms improve to ≤ grade 1, restart elotuzumab infusion at a rate of 0.5 mL/minute and gradually increase the rate by 0.5 mL/minute every 30 minutes as tolerated to the rate at which the infusion reaction occurred. May continue to escalate the rate if there is no recurrence of the infusion reaction (see Administration). Monitor vital signs every 30 minutes during and for 2 hours after the end of the infusion in patients who experience an infusion reaction. If the reaction recurs, discontinue the elotuzumab infusion and do not restart on that day. Severe infusion reactions may require therapy discontinuation and emergency management.

Reconstitution

Reconstitute the 300 mg vial with 13 mL of SWFI, and the 400 mg vial with 17 mL of SWFI (to a concentration of 25 mg/mL) with an 18-gauge or lower (eg, 17-gauge) needle. Slight back pressure may occur during reconstitution. Rotate the vial to dissolve the lyophilized powder (holding the vial upright). To dissolve any powder on the stopper or top of the vial, invert the vial several times; avoid vigorous agitation. Do not shake. The powder should dissolve in <10 minutes. After dissolution, allow the reconstituted vials to stand for 5 to 10 minutes (solution should be colorless to slightly yellow, clear to slightly opalescent). Discard if any particulate matter or discoloration is observed.

Each vial contains overfill to allow for withdrawal of 12 mL (300 mg vial) and 16 mL (400 mg vial), respectively. Withdraw appropriate dose from each vial (maximum of 12 mL from the 300 mg vial and 16 mL from the 400 mg vial). Further dilute with NS or D5W in a polyvinyl chloride or polyolefin infusion bag to a final concentration range of 1 to 6 mg/mL; the volume of diluent may be adjusted in order to not exceed 5 mL/kg of body weight. Do not mix with other medications.

Administration

For IV infusion only. Do not administer IV push or as a bolus. Premedicate with dexamethasone, acetaminophen, and an H₁- and H₂-blocker (see Dosing) approximately 45 to 90 minutes prior to administration. Infuse in an environment equipped to monitor for and manage infusion reactions. Administer with an infusion set and a sterile, non-pyrogenic, low protein-binding filter (0.2 to 1.2 micrometer) using an automated infusion pump. Do not mix with or infuse with other medications. Infusion should be completed within 24 hours of reconstitution. Monitor for infusion reaction. Interrupt infusion for grade 2 or higher infusion reactions; if the reaction resolves or improves to ≤ grade 1, may resume infusion (see Dosage Adjustment for Toxicity). Monitor vital signs every 30 minutes during and for 2 hours after the end of the infusion in patients who experience an infusion reaction.

Infusion rate:

10 mg/kg dose:

First infusion (Cycle 1, Dose 1): Infuse at 0.5 mL/minute for the first 30 minutes. If no infusion reactions occur, may increase the rate to 1 mL/minute for the next 30 minutes. If tolerated, may then increase the rate to 2 mL/minute until infusion completion (maximum rate: 2 mL/minute).

Second infusion (Cycle 1, Dose 2): If no infusion reactions occurred during the prior infusion, initiate at 3 mL/minute for the first 30 minutes. If tolerated, may then increase the rate to 4 mL/minute until infusion completion (maximum rate: 4 mL/minute).

Subsequent infusions (Cycle 1, Doses 3 and 4 and all subsequent infusions): If no infusion reactions occurred during the prior infusion, initiate and infuse at 5 mL/minute until completion (maximum rate: 5 mL/minute).

20 mg/kg dose:

First infusion (Dose 1): Initiate infusion at 3 mL/minute for the first 30 minutes. Infusion rates which were escalated to 5 mL/minute at the 10 mg/kg dose must be decreased to 3 mL/minute at the first infusion at 20 mg/kg dose. If no infusion reactions occur at 3 mL/minute, may increase the rate to 4 mL/minute until infusion completion (maximum rate: 4 mL/minute).

Second infusion (Dose 2): If no infusion reactions occurred during the prior infusion, initiate and infuse at 5 mL/minute until completion (maximum rate: 5 mL/minute).

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Protect from light (store in the original packaging until use); do not freeze or shake. Solutions diluted for infusion in NS or D5W may be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours (protected from light). A maximum of 8 hours of the 24 hour storage time may be at room temperature and room light. Infusion must be completed within 24 hours of lyophilized powder reconstitution.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Test Interactions

Elotuzumab may be detected on both serum protein electrophoresis (SPEP) and serum immunofixation assays used for multiple myeloma endogenous M-protein monitoring, and may affect the determination of complete response and disease progression of some patients with IgG kappa myeloma protein. A small peak in the early gamma region on SPEP that is IgG kappa on serum immunofixation may potentially be attributed to elotuzumab (especially when endogenous myeloma protein is IgA, IgM, IgD, or lambda light chain restricted).

Adverse Reactions

All incidences reported with combination therapy.

>10%:

Cardiovascular: Decreased heart rate (43% to 66%; <60 bpm), increased heart rate (23% to 48%; ≥100 bpm), altered blood pressure (systolic ≥160 mmHg: 18% to 33%; systolic <90 mmHg: 7% to 29%; diastolic ≥100 mmHg: 8% to 17%), peripheral edema (13%)

Central nervous system: Fatigue (62%), peripheral neuropathy (27%; grades 3/4: 4%), headache (15%)

Endocrine & metabolic: Hyperglycemia (20% to 89%), hypocalcemia (58% to 78%), hypoalbuminemia (65% to 73%), decreased serum bicarbonate (63%), hyponatremia (40%), hyperkalemia (32%), hypokalemia (23%), weight loss (14%)

Gastrointestinal: Diarrhea (18% to 47%), constipation (22% to 36%), decreased appetite (21%), vomiting (14%)

Hematologic & oncologic: Lymphocytopenia (10% to 99%; grades 3/4: 8% to 77%), leukopenia (80% to 91%; grades 3/4: 32% to 52%), thrombocytopenia (78% to 84%; grades 3/4: 17% to 19%)

Hepatic: Increased serum alkaline phosphatase (39%)

Immunologic: Antibody development (19% to 36%; neutralizing: 4% to 6%)

Infection: Infection (65% to 81%), opportunistic infection (10% to 22%), herpes zoster infection (5% to 14%), fungal infection (10%)

Neuromuscular & skeletal: Limb pain (16%), ostealgia (15%), muscle spasm (13%)

Ophthalmic: Cataract (12%)

Respiratory: Cough (34%), nasopharyngitis (25%), upper respiratory tract infection (23%), pneumonia (13% to 20%), respiratory tract infection (3% to 17%), dyspnea (15%), oropharyngeal pain (10%)

Miscellaneous: Fever (7% to 37%), infusion related reaction (3% to 10%)

1% to 10%:

Cardiovascular: Chest pain (≥5%), pulmonary embolism (3%)

Central nervous system: Hypoesthesia (≥5%), mood changes (≥5%)

Dermatologic: Night sweats (≥5%)

Hematologic & oncologic: Second primary malignant neoplasm (9%), malignant neoplasm of skin (4%), malignant solid tumor (4%), anemia (3%), malignant neoplasm (hematologic: 2%)

Hepatic: Hepatotoxicity (3%)

Hypersensitivity: Hypersensitivity reaction (≥5%)

Renal: Acute renal failure (3%)

Warnings/Precautions

Concerns related to adverse effects:

• Hepatotoxicity: Liver enzyme elevations (AST/ALT more than 3 times ULN, total bilirubin more than 2 times ULN, and alkaline phosphatase less than 2 times ULN) have occurred. Monitor liver function tests periodically; may require treatment interruption and/or discontinuation.
• Infection: Infections (including grade 3 and 4 infections) were reported in the majority of multiple myeloma patients treated in the clinical trials, including fatal infections. Monitor for opportunistic, fungal, herpes zoster, and other infections during therapy; treat promptly if infections occur.
• Infusion reactions: Infusion reactions (eg, fever, chills, hypertension) have been reported; all reactions were grade 3 or lower. Bradycardia and hypotension have also occurred during infusion. The majority of infusion reactions (~70%) occurred during the first dose. Premedicate with dexamethasone, H₁- and H₂-blockers, and acetaminophen prior to each dose. Administer in a facility with immediate access to resuscitative measures (eg, glucocorticoids, epinephrine, bronchodilators, and/or oxygen). May require treatment interruption, infusion rate modification, and/or discontinuation.
• Secondary malignancy: Invasive second primary malignancies have been reported. In one clinical trial, the rate of hematologic malignancies was the same between the elotuzumab/lenalidomide/dexamethasone group versus the lenalidomide/dexamethasone group. Solid tumors and skin cancer were reported more frequently in the elotuzumab arm versus the control group. Monitor for the development of secondary malignancies.

Disease-related concerns:

• Interference with determination of myeloma response: Elotuzumab (a human IgG kappa monoclonal antibody) may be detected on serum protein electrophoresis and immunofixation assays which monitor for endogenous M-protein. Interference with these assays by elotuzumab may affect the determination of complete response and disease progression in some patients with IgG kappa myeloma protein.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Monitoring Parameters

Liver function tests (periodically); signs/symptoms of infusion reactions (monitor vital signs every 30 minutes during and for 2 hours after the end of the infusion in patients who experience an infusion reaction), infections, and second primary malignancies

Pregnancy

Pregnancy Considerations

Animal reproduction studies have not been conducted. Elotuzumab is indicated for use in combination with lenalidomide or pomalidomide. Due to its potential to cause fetal harm, lenalidomide and pomalidomide are only available through a REMS program. Males and females of reproductive potential using these combinations must be able to comply with pregnancy testing and contraception requirements for lenalidomide or pomalidomide. Refer to the lenalidomide or pomalidomide monograph for additional information.

Patient Education

What is this drug used for?

• It is used to treat multiple myeloma.
• This drug is used with a steroid drug (dexamethasone) and either lenalidomide or pomalidomide. Talk with the doctor about the risks and side effects that may happen with those drugs.

Frequently reported side effects of this drug

• Loss of strength and energy
• Diarrhea
• Constipation
• Burning or numbness feeling
• Stuffy nose
• Sore throat
• Common cold symptoms
• Bone pain
• Muscle spasm
• Lack of appetite
• Painful extremities
• Vomiting
• Weight loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Shortness of breath
• Swelling of arms or legs
• Severe headache
• Dizziness
• Passing out
• Fast heartbeat
• Slow heartbeat
• Mole changes
• Skin growth
• Vision changes
• Chest pain
• Mood changes
• Night sweats
• Bruising
• Bleeding
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.