Elotuzumab

Elotuzumab is an immunostimulatory humanised IgG1 monoclonal antibody directed at SLAMF7, produced in NS0 cells by recombinant DNA technology. SLAMF7 is highly expressed on multiple myeloma cells whatever their cytogenetic abnormalities. It is also found on natural killer (NK) cells, normal plasma cells and some other immune cells (some T-cell subsets, monocytes, B cells, macrophages and plasmacytoid dendritic cells), but not on normal solid tissues or haematopoietic stem cells.

Mechanism of Action

• Direct NK-cell activation: elotuzumab activates NK cells through the SLAMF7 pathway and through Fc receptors, which enhances anti-myeloma activity in vitro.
• Targeting of myeloma cells: by binding SLAMF7 on myeloma cells and engaging Fc receptors on immune cells, it promotes killing of the myeloma cells by NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and by macrophage-mediated antibody-dependent cellular phagocytosis (ADCP).
• Combination partners: in non-clinical models, elotuzumab was synergistic with lenalidomide and with pomalidomide.

Pharmacokinetics

• Absorption: given intravenously, so it is immediately and completely bioavailable. Pharmacokinetics are non-linear: clearance falls as the dose rises from 0.5 to 20 mg/kg.
• Distribution: geometric mean volume of distribution at steady state is 5.7 L with lenalidomide and dexamethasone and 5.6 L with pomalidomide and dexamethasone.
• Metabolism: the metabolic pathway has not been characterised. As an IgG antibody it is expected to be broken down into small peptides and amino acids by catabolic pathways.
• Elimination: geometric mean total clearance at 10 mg/kg with lenalidomide and dexamethasone is 0.194 L/day at steady state. After treatment stops, concentrations fall to about 3% of the predicted steady-state maximum (about 97% washout, estimated as 5 half-lives) by 3 months.
• Special populations: clearance rises with body weight, which supports weight-based dosing, and with higher serum M-protein. Age, sex, race, baseline lactate dehydrogenase, albumin, renal impairment, mild hepatic impairment and co-administration with lenalidomide or pomalidomide and dexamethasone had no clinically important effect.

• With lenalidomide and dexamethasone: multiple myeloma in adult patients who have received at least one prior therapy.
• With pomalidomide and dexamethasone: relapsed and refractory multiple myeloma in adult patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and who have shown disease progression on the last therapy.

• Hypersensitivity to the active substance or to any of the excipients (sucrose, sodium citrate, citric acid monohydrate, polysorbate 80).
• The SmPCs of lenalidomide, pomalidomide and dexamethasone used with elotuzumab must be consulted before starting therapy; their contraindications also apply to the combination.

The safety data cover 682 patients with multiple myeloma treated with elotuzumab in eight clinical trials (451 with lenalidomide and dexamethasone, 128 with pomalidomide and dexamethasone and 103 with bortezomib and dexamethasone). Most reactions were mild to moderate (grade 1 or 2), and pneumonia is the most serious reaction. The frequencies below are the overall frequencies in the SmPC table; terms such as pneumonia, herpes zoster, lymphopenia and cough each group several related terms.

Very common (≥1/10): pneumonia, upper respiratory tract infection, nasopharyngitis, lymphopenia, headache, cough, diarrhoea, fatigue, pyrexia, weight decreased.

Common (≥1/100 to <1/10): herpes zoster, leukopenia, hypersensitivity, mood altered, hypoaesthesia, deep vein thrombosis, oropharyngeal pain, night sweats, chest pain, infusion-related reaction.

Uncommon (≥1/1,000 to <1/100): anaphylactic reaction.

Infusion-related reactions occur with elotuzumab, and their rate was much higher in patients who were not premedicated. In the main study of elotuzumab with lenalidomide and dexamethasone, some reactions occurred more often per patient-year than with lenalidomide and dexamethasone alone, for example diarrhoea, pyrexia, cough, headache, pneumonia and herpes zoster (see the SmPC for the rates).

• No pharmacokinetic interaction studies have been done. As a humanised monoclonal antibody, elotuzumab is not expected to be metabolised by cytochrome P450 or other drug-metabolising enzymes, so inhibition or induction of these enzymes by other medicines is not expected to affect it.
• Laboratory tests: elotuzumab can be detected on serum protein electrophoresis (SPEP) and serum immunofixation in myeloma patients and may interfere with response classification. It can produce a small early gamma peak that is IgG-kappa on immunofixation, which can affect the assessment of complete response, and possibly of relapse from complete response, in patients with IgG kappa myeloma protein. If additional peaks appear on immunofixation, a biclonal gammopathy should be excluded.
• Combination partners: the SmPCs of lenalidomide, pomalidomide and dexamethasone must be consulted before starting; their interactions and conditions of use apply to the combination.

Elotuzumab therapy is started and supervised by physicians experienced in treating multiple myeloma. Empliciti is for intravenous use only; the powder is reconstituted and diluted before the infusion (see section 6.6 of the SmPC). In both combinations, treatment continues until disease progression or unacceptable toxicity.

Premedication

To prevent infusion-related reactions (IRRs), give the following 45–90 minutes before every infusion:

• dexamethasone 8 mg intravenously;
• an H1 blocker: diphenhydramine 25–50 mg orally or intravenously, or an equivalent H1 blocker;
• an H2 blocker: ranitidine 50 mg intravenously or 150 mg orally, or an equivalent H2 blocker;
• paracetamol 650–1,000 mg orally.

Dose with Lenalidomide and Dexamethasone (28-Day Cycles)

• Elotuzumab: 10 mg/kg body weight intravenously every week (days 1, 8, 15 and 22) in cycles 1 and 2, then every 2 weeks (days 1 and 15) from cycle 3.
• Lenalidomide: 25 mg orally once daily on days 1–21 of each cycle, and at least 2 hours after the elotuzumab infusion on days when both are given.
• Dexamethasone: on elotuzumab days, 28 mg orally once daily 3–24 hours before the infusion plus 8 mg intravenously 45–90 minutes before it. On days when dexamethasone is scheduled but elotuzumab is not (days 8 and 22 of cycle 3 onwards), 40 mg orally.

Dose with Pomalidomide and Dexamethasone (28-Day Cycles)

• Elotuzumab: 10 mg/kg intravenously every week (days 1, 8, 15 and 22) in cycles 1 and 2, then 20 mg/kg on day 1 of each cycle.
• Pomalidomide: 4 mg orally once daily on days 1–21 of each cycle, and at least 2 hours after the elotuzumab infusion on days when both are given.
• Dexamethasone, patients aged 75 years or younger: on elotuzumab days, 28 mg orally 3–24 hours before the infusion plus 8 mg intravenously 45–90 minutes before it; on days with dexamethasone but no elotuzumab (days 8, 15 and 22 of cycle 3 onwards), 40 mg orally.
• Dexamethasone, patients older than 75 years: on elotuzumab days, 8 mg orally 3–24 hours before the infusion plus 8 mg intravenously 45–90 minutes before it; on days with dexamethasone but no elotuzumab, 20 mg orally.

Infusion Rate

• 10 mg/kg dose: start at 0.5 mL/min and increase stepwise if well tolerated, never above 5 mL/min. Cycle 1, dose 1: 0.5 mL/min for 0–30 minutes, 1 mL/min for 30–60 minutes, then 2 mL/min until the end. Cycle 1, dose 2: 3 mL/min for 0–30 minutes, then 4 mL/min until the end. From cycle 1, dose 3 onwards: 5 mL/min.
• 20 mg/kg dose: start at 3 mL/min. First dose: 3 mL/min for 0–30 minutes, then 4 mL/min until the end. Later doses: 5 mL/min. A patient who had reached 5 mL/min on the 10 mg/kg dose goes back to 3 mL/min for the first 20 mg/kg infusion.

Management of Infusion-Related Reactions

• If a reaction of grade 2 or higher occurs, interrupt the infusion. When it has fallen to grade 1 or lower, restart at 0.5 mL/min and raise the rate by 0.5 mL/min every 30 minutes as tolerated, up to the rate at which the reaction occurred. If it does not recur, the usual escalation can be resumed.
• After a reaction, check vital signs every 30 minutes for 2 hours after the end of the infusion.
• If the reaction recurs, stop the infusion and do not restart it that day. Very severe reactions (grade 3 or higher) may require permanent discontinuation and emergency treatment.

Dose Delay, Interruption or Discontinuation

If one medicine in the regimen is delayed, interrupted or stopped, the others may continue as scheduled. If dexamethasone is delayed or stopped, whether to give elotuzumab is a matter of clinical judgement (for example the risk of hypersensitivity).

Special Populations

• Elderly: no elotuzumab dose adjustment above 65 years. Data are very limited in patients aged 85 or over. The dexamethasone dose with pomalidomide depends on age (75 years or younger, or older than 75).
• Renal impairment: no adjustment in mild, moderate or severe impairment, or in end-stage renal disease requiring dialysis.
• Hepatic impairment: no adjustment in mild impairment. It has not been studied in moderate or severe impairment (defined in the SmPC by bilirubin and AST).
• Children and adolescents: there is no relevant use in the paediatric population for multiple myeloma.

Infusion-Related Reactions

Premedication with dexamethasone, an H1 blocker, an H2 blocker and paracetamol is mandatory before each infusion. Reactions of grade 2 or higher call for interruption of the infusion and medical and supportive measures. Patients with mild or moderate reactions may receive elotuzumab at a reduced infusion rate with close monitoring. See Administration and Dosage for the restart rules.

Infections

The incidence of all infections, including pneumonia, was higher in patients treated with elotuzumab. Patients should be monitored and infections managed with standard treatment.

Second Primary Malignancies

In the study of elotuzumab with lenalidomide and dexamethasone against lenalidomide and dexamethasone alone, second primary malignancies, specifically solid tumours and non-melanoma skin cancer, were more frequent with elotuzumab. These malignancies are known to be associated with lenalidomide exposure, which was longer in the elotuzumab arm. The rate of haematological malignancies was the same in both arms. Patients should be monitored for second primary malignancies.

Combination Therapy and Traceability

The conditions of use of the medicines given with elotuzumab also apply, and their SmPCs must be consulted before starting. Because it is a biological medicinal product, the name and batch number of the administered product should be clearly recorded.

Pregnancy, Contraception, Breastfeeding and Fertility

• Women of childbearing potential: elotuzumab should not be used unless the woman’s clinical condition requires it. Effective contraception is needed during treatment and for 120 days afterwards.
• Men: effective contraception during treatment and for 180 days afterwards if the partner is pregnant or of childbearing potential and not using effective contraception.
• Pregnancy: there is no human experience with elotuzumab in pregnancy, and no animal data on reproductive toxicity because no adequate animal model exists. It should not be used in pregnancy unless the clinical condition requires it. When given with lenalidomide or pomalidomide there is a risk of foetal harm, including severe life-threatening birth defects, so the pregnancy prevention programme of the partner medicine (including testing and contraception) must be followed. Lenalidomide and pomalidomide are present in blood and sperm; see their SmPCs.
• Breastfeeding: elotuzumab is not expected to be excreted into human milk, but breastfeeding should be stopped because of lenalidomide or pomalidomide.
• Fertility: studies have not been done, so the effect on male and female fertility is unknown.

Sodium

Each vial contains 3.92 mg (300 mg vial) or 5.23 mg (400 mg vial) of sodium, equivalent to 0.2% or 0.3% of the WHO recommended maximum daily intake of 2 g for an adult.

Effect on Driving

Elotuzumab is not expected to influence the ability to drive or use machines. Patients who have an infusion-related reaction should not drive or use machines until the symptoms go away.

Store unopened vials in a refrigerator at 2–8 °C, in the original package to protect from light, and do not freeze. Keep the cold chain intact during transport and storage.

After reconstitution the solution is moved from the vial into the infusion bag immediately. Chemical and physical stability of the reconstituted and diluted solution has been shown for 24 hours at 2–8 °C protected from light. From a microbiological point of view it should be used immediately; if not, in-use times and conditions are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C protected from light. Do not freeze it. It may be kept for a maximum of 8 hours of that 24 hours at 20–25 °C in room light, and this 8-hour period includes the time of administration.

Each pack holds one 20 mL Type I glass vial with a butyl stopper and aluminium seal, containing 300 mg (ivory flip-off button) or 400 mg (blue flip-off button).

Unopened vial: 4 years. After reconstitution and dilution: see Storage Conditions (24 hours at 2–8 °C protected from light).

Prescription only (Rx), for use under the supervision of physicians experienced in treating multiple myeloma. Empliciti is infused in a hospital or clinic, together with its combination partners and premedication, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery.