ELREXFIO

Antineoplastic Bispecific Antibodies Targeting BCMA and CD3

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Elranatamab is a clear to slightly opalescent, colorless to pale brown liquid solution; do not use if the solution is discolored or contains particulate matter.

Elranatamab is administered by a health care professional in a facility with medical personnel and equipment capable of managing severe reactions.
Premedicate patients with a corticosteroid (e.g., dexamethasone), diphenhydramine, and antipyretic (i.e., acetaminophen) 1 hour prior to the injection as recommended.
Preparation:
Elranatamab is available as single-dose 44 mg/1.1 mL (40 mg/mL) or 76 mg/1.9 mL (40 mg/mL) solution vials; further vial dilution is not necessary.
Remove the appropriate concentration vial from the refrigerator and allow the vial to warm to ambient temperature (15 to 30 degrees C; 59 to 86 degrees F); do not warm the vial any other way.
Using a stainless-steel injection needle (30G or wider), withdraw the appropriate volume from the vial into a syringe made from polypropylene or polycarbonate material.
The appropriate elranatamab volume is based on vial concentration and type of dose as follows:
44 mg/1.1 mL (40 mg/mL) vial: Withdraw 0.3 mL for the 12-mg (step-up dose 1) and 0.8 mL for the 32-mg (step-up dose 2) doses.76 mg/1.9 mL (40 mg/mL) vial: Withdraw 1.9 mL for the 76-mg dose.
Storage of prepared syringe: If the dose is not given immediately, may store between 2 and 30 degrees C (36 to 86 degrees F) for up to 4 hours.
Subcutaneous injection:
Inject the elranatamab dose into the subcutaneous tissue of the abdomen (preferred site) or other appropriate site (e.g., thigh).
Do not inject into tattoos, scars, or areas where the skin is red, bruised, tender, hard, or not intact.

lymphopenia / Delayed / 84.0-84.0
neutropenia / Delayed / 51.0-51.0
anemia / Delayed / 43.0-43.0
leukopenia / Delayed / 40.0-40.0
thrombocytopenia / Delayed / 32.0-32.0
infection / Delayed / 31.0-31.0
sepsis / Delayed / 11.0-11.0
heart failure / Delayed / 0-10.0
nephrotoxicity / Delayed / 0-10.0
thrombosis / Delayed / 0-10.0
hypokalemia / Delayed / 8.0-8.0
neurotoxicity / Early / 7.0-7.0
fatigue / Early / 6.0-6.0
elevated hepatic enzymes / Delayed / 3.8-6.0
hypoalbuminemia / Delayed / 6.0-6.0
dyspnea / Early / 3.3-3.3
fever / Early / 2.7-2.7
musculoskeletal pain / Early / 2.7-2.7
encephalopathy / Delayed / 2.7-2.7
hypogammaglobulinemia / Delayed / 2.2-2.2
bleeding / Early / 1.6-1.6
edema / Delayed / 1.1-1.1
diarrhea / Early / 1.1-1.1
anorexia / Delayed / 1.1-1.1
cardiogenic shock / Early / 0-1.0
cardiopulmonary reaction / Rapid / 0-1.0
pulmonary embolism / Delayed / 0-1.0
hyperbilirubinemia / Delayed / 0.5-0.5
cytokine release syndrome / Rapid / 0.5-0.5
peripheral neuropathy / Delayed / 0.5-0.5
headache / Early / 0.5-0.5
Guillain-Barre syndrome / Delayed / 0.5-0.5
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known

constipation / Delayed / 15.0-15.0
antibody formation / Delayed / 8.9-8.9
erythema / Early / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
sinus tachycardia / Rapid / Incidence not known
hypotension / Rapid / Incidence not known
ataxia / Delayed / Incidence not known
confusion / Early / Incidence not known
impaired cognition / Early / Incidence not known
delirium / Early / Incidence not known
hallucinations / Early / Incidence not known
memory impairment / Delayed / Incidence not known

injection site reaction / Rapid / 37.0-37.0
rash / Early / 25.0-25.0
cough / Delayed / 24.0-24.0
nausea / Early / 22.0-22.0
vomiting / Early / 14.0-14.0
insomnia / Early / 13.0-13.0
xerosis / Delayed / 13.0-13.0
abdominal pain / Early / 0-10.0
maculopapular rash / Early / Incidence not known
chills / Rapid / Incidence not known
weakness / Early / Incidence not known
paresthesias / Delayed / Incidence not known
parosmia / Delayed / Incidence not known
dysesthesia / Delayed / Incidence not known
lethargy / Early / Incidence not known
tremor / Early / Incidence not known
agitation / Early / Incidence not known
drowsiness / Early / Incidence not known
hypoesthesia / Delayed / Incidence not known

Cytokine release syndrome (CRS) has been reported with elranatamab; cases may be fatal or life-threatening. Evaluate for and treat other causes of fever, hypoxia, and hypotension. To reduce the risk of CRS, administer elranatamab according to a step-up dosing schedule and give pretreatment medications as follows: dexamethasone 20 mg PO/IV or equivalent, diphenhydramine 25 mg PO or equivalent, and acetaminophen 650 mg PO or equivalent at about 1 hour prior to each dose for a total of 3 doses in the step-up dosing schedule. Continue premedications with subsequent elranatamab doses as recommended in patients who develop CRS or have therapy delayed for other toxicity. Hospitalization is recommended for 48 hours following the first step-up dose and for 24 hours following the second step-up dose. Interruption or discontinuation of therapy may be necessary in patients who develop CRS; evaluate the need for hospitalization, supportive care, and further management (using current practice guidelines) in patients with severe CRS.

Severe neurotoxicity (e.g., immune effector cell-associated neurotoxicity syndrome (ICANS), encephalopathy, Guillain-Barre syndrome) has been reported with elranatamab therapy; cases may be serious or life-threatening. Rule out other causes of neurologic symptoms. ICANS may occur concurrently with cytokine release syndrome (CRS) or after CRS resolves. Monitor patients for signs and symptoms of neurologic toxicity during treatment. Therapy interruption, corticosteroid administration, or permanent discontinuation of therapy may be necessary in patients who develop neurotoxicity. Consider a neurology (or other applicable specialty) consult for further evaluation and management (e.g., non-sedating, anti-seizure medication such as levetiracetam for seizure prophylaxis). Evaluate the need for hospitalization, supportive care, and further management (using current practice guidelines) in patients with severe neurotoxicity

ELREXFIO

Rx

Bispecific BCMA-directed CD3 T-cell engaging antibody
Used in adult patients with heavily pretreated relapsed or refractory multiple myeloma
Boxed warning for cytokine release syndrome and severe neurologic toxicity

Step-up dosing schedule: dose 1, 12 mg subcutaneously on day 1; dose 2, 32 mg subcutaneously on day 4 (maintain a minimum of 2 days between step-up dose 1 and 2); and first treatment dose, 76 mg subcutaneously on day 8 (maintain a minimum of 2 days between step-up dose 2 and the first treatment dose). At 1 week after the first treatment dose, give 76 mg subcutaneously once weekly through week 24. Maintain a minimum of 6 days between treatment doses. Starting on week 25, give 76 mg subcutaneously every 2 weeks until disease progression in patients who received at least 24 weeks of elranatamab treatment and achieved (and maintained for at least 2 months) a partial response or better. Therapy interruption or discontinuation may be necessary in patients who develop toxicity. Administer premedications (i.e, dexamethasone 20 mg PO or IV or equivalent, diphenhydramine 25 mg PO or equivalent, and acetaminophen 650 mg PO or equivalent) approximately 1 hour prior to each dose in the step-up dosing schedule. Premedication with subsequent elranatamab doses may be required in patients who repeat doses within the step-up dosing schedule due to dose delays or experience cytokine release syndrome. Following treatment with elranatamab, the blinded independent central review-assessed objective response rate (ORR) was 61% (complete response or better, 35%) in a cohort of patients with relapsed or refractory multiple myeloma who had not previously received BCMA-directed therapy (n = 123) in a multicenter, phase 2 (MagnetisMM-3) trial. At a median follow-up time of 14.7 (range, 0.2 to 25.1) months, the median duration of response (DOR) had not been reached in responding patients; additionally, the median progression-free and overall survival times were not reached. Patients (median age, 68 [range, 36 to 89] years; high-risk cytogenetics, 25.2%) had received a median of 5 (range, 2 to 22) prior lines of therapy; 70.7% of patients had previously received a stem-cell transplantation. In the MagnetisMM-3 trial, the ORR was 33.3% in a cohort of patients who had received prior BCMA-directed therapy (n = 64). At a median follow-up time of 10.2 months, the median DOR was not reached; the DOR rate at 9 months was 84.3%. Patients had received a median of 8 (range, 4 to 19) prior lines of therapy; 32% of patients had received prior CAR-T cell therapy and 73% of patients had received prior a BCMA-directed antibody drug conjugate.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no initial dosage adjustments are needed. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe hepatotoxicity.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no initial dosage adjustments are needed.

Monitor for toxicity of CYP substrates, especially after starting elranatamab therapy, for 2 weeks after the 32-mg dose, and during/after cytokine release syndrome. Elranatamab related-cytokine release may suppress CYP activity.

ELREXFIO Subcutaneous Inj Sol: 1mL, 40mg

76 mg once per week subcutaneously.

76 mg once per week subcutaneously.

Safety and efficacy not established.

Safety and efficacy not established.

Safety and efficacy not established.

Elranatamab is a bispecific T-cell engaging (BiTE) antibody that works by binding the CD3 receptor expressed on the surface of T-cells to the B-cell maturation antigen (BCMA) expressed on the surface of plasma cells, plasmablasts, and multiple myeloma cells. It is a humanized immunoglobulin 2-alanine kappa antibody derived from 2 monoclonal antibodies (mAbs), an anti-BCMA mAb and an anti-CD3 mAb. Each of these mAbs has a distinct heavy chain and a distinct light chain to the bispecific elranatamab; the resulting 4-chain bispecific antibody is covalently linked via 5 inter-chain disulfide bonds. Elranatamab is produced from 2 Chinese Hamster Ovary (CHO) cell lines using recombinant DNA technology. The binding of CD3 and BCMA activates T-cells causing a release of proinflammatory cytokines resulting in the lysis of multiple myeloma cells.

Elranatamab is administered subcutaneously. It has a steady-state geometric mean volume of distribution of 7.76 L (coefficient of variation (CV), 33%). At week 24 of elranatamab 76 mg weekly dosing, the geometric mean clearance is 0.324 L/day (CV, 100%) and the mean elimination half-life is 22 days (64%). It appears that elranatamab is metabolized into small peptides by catabolic pathways.
Affected cytochrome P450 isoenzymes and drug transporters: CYP substratesElranatamab may cause a cytokine release that suppresses CYP enzyme activity and increases the exposure of CYP substrates.

The mean bioavailability of elranatamab is 56.2% when administered subcutaneously. The pharmacokinetic parameters of elranatamab increase proportionally over a dosage range of 6 to 76 mg. In patients with relapsed or refractory multiple myeloma who achieved a response, the geometric mean Cmax values were 33.6 (coefficient of variation (CV), 48%) and 20.1 (CV, 55%) micrograms/mL following elranatamab weekly dosing (at week 24 of 76 mg dosing) and biweekly dosing (at approximately week 48), respectively. Additionally, the median Tmax was 7 (range, 3 to 7) days.

Elranatamab may cause fetal harm if administered during pregnancy based on its mechanism of action. Pregnant patients should be apprised of the potential hazard to the fetus. There are no available data with elranatamab use in pregnant women; animal reproductive and developmental toxicity studies have not been conducted. Elranatamab causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. Additionally, elranatamab-induced B-cell lymphopenia may occur in the developing fetus exposed in-utero. Human immunoglobulin G is known to cross into the placenta; therefore, elranatamab may be transmitted from the mother to the developing fetus. Due to a risk of hypogammaglobulinemia, consider assessing immunoglobulin levels in neonates of mothers treated with teclistamab.

Due to the potential for serious adverse reactions in the breastfed child, advise patients to avoid breast-feeding during and for 4 months after the last elranatamab dose. It is not known if elranatamab is secreted in human milk or if it has effects on milk production or the breastfed child. Human immunoglobulin (IgG) is excreted in human milk.