Elranatamab-bcmm
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, DMD, MD[2]
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Black Box Warning
|
WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITY INCLUDING IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
See full prescribing information for complete Boxed Warning.
span style="clear;">SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING.
•Cytokine Release Syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving ELREXFIO. Initiate treatment with ELREXFIO step-up dosing schedule to reduce the risk of CRS. Withhold ELREXFIO until CRS resolves or permanently discontinue based on severity. (2.2, 2.5, 5.1) •Neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), and serious and life-threatening reactions, can occur in patients receiving ELREXFIO. Monitor patients for signs and symptoms of neurologic toxicity, including ICANS, during treatment. Withhold ELREXFIO until the neurologic toxicity resolves or permanently discontinues based on severity. •ELREXFIO is available only through a restricted program called the ELREXFIO Risk Evaluation and Mitigation Strategy (REMS). |
Overview
Elranatamab-bcmm is a bispecific B-cell maturation antigen (BCMA)- that is FDA approved for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include {{{adverseReactions}}}.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
2.1 Important Dosing Information Administer ELREXFIO subcutaneously according to the step-up dosing schedule to reduce the incidence and severity of cytokine release syndrome (CRS).
Administer pre-treatment medications prior to each dose in the ELREXFIO step-up dosing schedule, which includes step-up dose 1, step-up dose 2, and the first treatment dose as recommended [see DOSAGE AND ADMINISTRATION (2.2, 2.3)].
ELREXFIO should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and neurologic toxicity, including ICANS [see WARNINGS AND PRECAUTIONS (5.1, 5.2)].
Due to the risk of CRS, patients should be hospitalized for 48 hours after administration of the first step-up dose, and for 24 hours after administration of the second step-up dose.
2.2 Recommended Dosage For subcutaneous injection only.
The recommended dosing schedule for ELREXFIO is provided in Table 1. The recommended dosages of ELREXFIO subcutaneous injection are: step-up dose 1 of 12 mg on Day 1, step-up dose 2 of 32 mg on Day 4, followed by the first treatment dose of 76 mg on Day 8, and then 76 mg weekly thereafter through week 24.
For patients who have received at least 24 weeks of treatment with ELREXFIO and have achieved a response [partial response (PR) or better] and maintained this response for at least 2 months, the dose interval should transition to an every two-week schedule.
Continue treatment with ELREXFIO until disease progression or unacceptable toxicity.
Administer pre-treatment medications before each dose in the ELREXFIO step-up dosing schedule, which includes step-up dose 1, step-up dose 2, and the first treatment dose as recommended.
2.3 Recommended Pre-treatment Medications Administer the following pre-treatment medications approximately 1 hour before the first three doses of ELREXFIO in the step-up dosing schedule, which includes step-up dose 1, step-up dose 2, and the first treatment dose as described in Table 1 to reduce the risk of CRS [see WARNINGS AND PRECAUTIONS (5.1)]:
• acetaminophen (or equivalent) 650 mg orally • dexamethasone (or equivalent) 20 mg orally or intravenously • diphenhydramine (or equivalent) 25 mg orally 2.4 Restarting ELREXFIO After Dosage Delay If a dose of ELREXFIO is delayed, restart therapy based on the recommendations listed in Table 2 and resume the dosing schedule accordingly
2.5 Dosage Modifications for Adverse Reactions Dosage reductions of ELREXFIO are not recommended.
Dosage delays may be required to manage toxicities related to ELREXFIO [see WARNINGS AND PRECAUTIONS (5)]. Recommendations on restarting ELREXFIO after a dose delay are provided in Table 2.
See TABLE 3 and TABLE 4 for recommended actions for adverse reactions of CRS and ICANS, respectively. See TABLE 5 for recommended actions for neurologic toxicity excluding ICANS and TABLE 6 for recommended actions for other adverse reactions following administration of ELREXFIO. Consider further management per current practice guidelines.
Management of CRS, Neurologic Toxicity Including ICANS
Cytokine Release Syndrome (CRS)
Management recommendations for CRS are summarized in Table 3.
Identify CRS based on clinical presentation [see WARNINGS AND PRECAUTIONS (5.1)]. Evaluate and treat other causes of fever, hypoxia, and hypotension.
If CRS is suspected, withhold ELREXFIO until CRS resolves. Manage CRS according to the recommendations in Table 3 and consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS. Consider laboratory testing to monitor for disseminated intravascular coagulation (DIC), hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function.
Neurologic Toxicity Including ICANS
Management recommendations for ICANS and neurologic toxicity are summarized in Table 4 and Table 5.
At the first sign of neurologic toxicity, including ICANS, withhold ELREXFIO and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for severe or life-threatening neurologic toxicities, including ICANS [see WARNINGS AND PRECAUTIONS (5.2)]. Manage ICANS according to the recommendations in Table 4 and consider further management per current practice guidelines.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Elranatamab-bcmm FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
None
Warnings
|
WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITY INCLUDING IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
See full prescribing information for complete Boxed Warning.
span style="clear;">SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING.
•Cytokine Release Syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving ELREXFIO. Initiate treatment with ELREXFIO step-up dosing schedule to reduce the risk of CRS. Withhold ELREXFIO until CRS resolves or permanently discontinue based on severity. (2.2, 2.5, 5.1) •Neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), and serious and life-threatening reactions, can occur in patients receiving ELREXFIO. Monitor patients for signs and symptoms of neurologic toxicity, including ICANS, during treatment. Withhold ELREXFIO until the neurologic toxicity resolves or permanently discontinues based on severity. •ELREXFIO is available only through a restricted program called the ELREXFIO Risk Evaluation and Mitigation Strategy (REMS). |
Cytokine Release Syndrome (CRS) ELREXFIO can cause CRS, including life-threatening or fatal reactions.
In the clinical trial, CRS occurred in 58% of patients who received ELREXFIO at the recommended dosing schedule, with Grade 1 CRS in 44% of patients, Grade 2 CRS in 14% of patients, and Grade 3 CRS in 0.5% of patients. Recurrent CRS occurred in 13% of patients. Most patients experienced CRS after the first step-up dose (43%) or the second step-up dose (19%), with 7% of patients having CRS after the first treatment dose and 1.6% of patients after a subsequent dose. The median time to onset of CRS was 2 (range: 1 to 9) days after the most recent dose, with a median duration of 2 (range: 1 to 19) days.
Clinical signs and symptoms of CRS may include but are not limited to, fever, hypoxia, chills, hypotension, tachycardia, headache, and elevated liver enzymes.
Initiate therapy according to the ELREXFIO step-up dosing schedule to reduce the risk of CRS and monitor patients following the administration of ELREXFIO accordingly Administer pre-treatment medications before each dose in the step-up dosing schedule to reduce the risk of CRS.
Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, evaluate patients immediately for hospitalization. Manage CRS according to the recommendations and consider further management per current practice guidelines. Withhold or permanently discontinue ELREXFIO based on severity.
ELREXFIO is available only through a restricted program under a REMS.
5.2 Neurologic Toxicity, Including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) ELREXFIO can cause serious or life-threatening neurologic toxicity, including ICANS.
In the clinical trial, neurologic toxicity occurred in 59% of patients who received ELREXFIO at the recommended dosing schedule [see DOSAGE AND ADMINISTRATION (2.2)], with Grade 3 or 4 neurologic toxicity occurring in 7% of patients. Neurologic toxicities included headache (18%), encephalopathy (15%), motor dysfunction (13%), sensory neuropathy (13%), and Guillain-Barré Syndrome (0.5%).
In the clinical trial, ICANS occurred in 3.3% of patients who received ELREXFIO at the recommended dosing schedule . Most patients had ICANS after the first step-up dose (2.7%), 1 (0.5%) patient had ICANS after the second step-up dose, and 1 (0.5%) patient had ICANS after subsequent dose(s). Recurrent ICANS occurred in 1.1% of patients. The median time to onset was 3 (range: 1 to 4) days after the most recent dose, with a median duration of 2 (range: 1 to 18) days. The most frequent clinical manifestations of ICANS included a depressed level of consciousness and Grade 1 or Grade 2 Immune Effector Cell-Associated Encephalopathy (ICE) scores. The onset of ICANS can be concurrent with CRS, following the resolution of CRS, or in the absence of CRS.
Counsel patients to seek medical attention should signs or symptoms of neurologic toxicity occur. Monitor patients for signs and symptoms of neurologic toxicities during treatment with ELREXFIO. At the first sign of neurologic toxicity, including ICANS, evaluate and treat patients immediately based on severity. Withhold or permanently discontinue ELREXFIO based on severity per recommendations and consider further management per current practice guidelines.
Due to the potential for neurologic toxicity including ICANS, patients receiving ELREXFIO are at risk of depressed levels of consciousness. Advise patients not to drive or operate heavy or potentially dangerous machinery for 48 hours after completing each of the 2 step-up doses and the first treatment dose within the ELREXFIO step-up dosing schedule and in the event of new onset of any neurological toxicity symptoms until symptoms resolve.
ELREXFIO is available only through a restricted program under a REMS.
ELREXFIO REMS ELREXFIO is available only through a restricted program under a REMS called the ELREXFIO REMS because of the risks of CRS and neurologic toxicity, including ICANS [see WARNINGS AND PRECAUTIONS (5.1, 5.2)].
Notable requirements of the ELREXFIO REMS include the following:
• Prescribers must be certified with the program by enrolling and completing training. • Prescribers must counsel patients receiving ELREXFIO about the risk of CRS and neurologic toxicity, including ICANS, and provide patients with ELREXFIO Patient Wallet Card. • Pharmacies and healthcare settings that dispense ELREXFIO must be certified with the ELREXFIO REMS program and must verify prescribers are certified through the ELREXFIO REMS program. • Wholesalers and distributers must only distribute ELREXFIO to certified pharmacies or healthcare settings. Further information about the ELREXFIO REMS program is available at WWW.ELREXFIOREMS.COM or by telephone at 1‑844‑923‑7845.
5.4 Infections ELREXFIO can cause severe, life-threatening, or fatal infections. In the clinical trial, in patients who received ELREXFIO according to the recommended dosing schedule, serious infections, including opportunistic infections, occurred in 42% of patients, with Grade 3 or 4 infections in 31%, and fatal infections in 7%. The most common serious infections reported (≥5%) were pneumonia and sepsis.
Do not initiate treatment with ELREXFIO in patients with active infections. Monitor patients for signs and symptoms of infection before and during treatment with ELREXFIO and treat appropriately. Withhold or permanently discontinue ELREXFIO based on severity. Administer prophylactic antimicrobial and anti-viral medications according to current practice guidelines. Consider treatment with subcutaneous or intravenous immunoglobulin (IVIG) as appropriate.
Neutropenia ELREXFIO can cause neutropenia and febrile neutropenia. In patients who received ELREXFIO at the recommended dose in the clinical trial, decreased neutrophils occurred in 62% of patients, with Grade 3 or 4 decreased neutrophils in 51%. Febrile neutropenia occurred in 2.2% of patients.
Monitor complete blood cell counts at baseline and periodically during treatment. Provide supportive care according to current practice guidelines. Monitor patients with neutropenia for signs of infection. Withhold ELREXFIO based on severity.
Hepatotoxicity ELREXFIO can cause hepatotoxicity. In the clinical trial, elevated ALT occurred in 36% of patients, with Grade 3 or 4 ALT elevation occurring in 3.8%; elevated AST occurred in 40% of patients, with Grade 3 or 4 AST elevation occurring in 6%. Grade 3 or 4 total bilirubin elevations occurred in 0.5% of patients. Liver enzyme elevation can occur with or without concurrent CRS.
Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold ELREXFIO or consider permanent discontinuation of ELREXFIO based on severity.
Embryo-Fetal Toxicity Based on its mechanism of action, ELREXFIO may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ELREXFIO and for 4 months after the last dose.
Adverse Reactions
Clinical Trials Experience
The following adverse reactions are discussed elsewhere in the labeling:
•Cytokine Release Syndrome •Neurologic Toxicity, Including ICANS •Infections •Neutropenia •Hepatotoxicity
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Relapsed/Refractory Multiple Myeloma
MagnetisMM-3
The safety of ELREXFIO was evaluated in MagnetisMM-3 [see CLINICAL STUDIES (14)]. The safety population described (n = 183) includes patients who received the recommended dosage regimen of 12 mg subcutaneously on Day 1, 32 mg on Day 4, and 76 mg once weekly starting on Day 8. Among patients who received ELREXFIO, 42% were exposed for 6 months or longer and 9% were exposed for one year or longer.
The median age of patients who received ELREXFIO was 68 years (range: 36 to 88 years); 48% were female; 61% were White, 10% were Hispanic/Latino, 9% were Asian, and 6% were Black or African American.
Serious adverse reactions occurred in 68% of patients who received ELREXFIO at the recommended dosing schedule. Serious adverse reactions in >2% of patients included pneumonia (25%), sepsis (13%), CRS (13%), upper respiratory tract infection (4.4%), acute kidney injury (3.8%), urinary tract infection (3.3%), COVID-19 (3.3%), encephalopathy (3.3%), pyrexia (2.2%), and febrile neutropenia (2.2%). Fatal adverse reactions occurred in 10% of patients including pneumonia (3.3%), sepsis (2.7%), acute respiratory distress syndrome (0.5%), cardio-respiratory arrest (0.5%), cardiogenic shock (0.5%), cardiopulmonary failure (0.5%), COVID-19 (0.5%), failure to thrive (0.5%), and pulmonary embolism (0.5%).
Permanent discontinuations of ELREXFIO due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of ELREXFIO in >2% of patients included septic shock (2.2%).
Dosage interruptions of ELREXFIO due to an adverse reaction occurred in 73% of patients. Adverse reactions that resulted in dose interruptions of ELREXFIO in >5% of patients included neutropenia, pneumonia, COVID-19, upper respiratory tract infection, thrombocytopenia, and anemia.
The most common adverse reactions (≥20%) were CRS, fatigue, injection site reaction, diarrhea, upper respiratory tract infection, musculoskeletal pain, pneumonia, decreased appetite, rash, cough, nausea, and pyrexia. The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased white blood cells, and decreased platelets.
Clinically relevant adverse reactions in <10% of patients who received ELREXFIO included ICANS, febrile neutropenia, Guillain-Barré syndrome, abdominal pain, acute kidney injury, COVID-19, cardiac failure, congestion, and thrombosis.
Postmarketing Experience
There is limited information regarding Elranatamab-bcmm Postmarketing Experience in the drug label.
Drug Interactions
For certain CYP substrates, minimal changes in the concentration may lead to serious adverse reactions. Monitor for toxicity or drug concentrations of such CYP substrates when co-administered with ELREXFIO.
ELREXFIO causes the release of cytokines that may suppress the activity of cytochrome P450 (CYP) enzymes, resulting in increased exposure to CYP substrates. Increased exposure to CYP substrates is more likely to occur after the first dose of ELREXFIO on Day 1 and up to 14 days after the 32 mg dose on Day 4 and during and after CRS
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): Risk Summary
Based on the mechanism of action, ELREXFIO may cause fetal harm when administered to a pregnant woman. There are no available data on the use of ELREXFIO in pregnant women to evaluate for a drug-associated risk. No animal reproductive or developmental toxicity studies have been conducted with ELREXFIO. Elranatamab-bcmm causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on the finding of B-cell depletion in non-pregnant animals, elranatamab-bcmm can cause B-cell lymphocytopenia in infants exposed to elranatamab-bcmm in-utero. Human immunoglobulin (IgG) is known to cross the placenta after the first trimester of pregnancy; therefore, elranatamab-bcmm has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus.
ELREXFIO is associated with hypogammaglobulinemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with ELREXFIO should be considered.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Elranatamab-bcmm in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Elranatamab-bcmm during labor and delivery.
Nursing Mothers
Risk Summary
There are no data on the presence of elranatamab-bcmm in human milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk.
Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ELREXFIO and for 4 months after the last dose
Pediatric Use
The safety and effectiveness of ELREXFIO in pediatric patients have not been established.
Geriatic Use
Of the 183 patients with relapsed or refractory multiple myeloma treated with ELREXFIO in MagnetisMM-3 at the recommended dosage, 62% were 65 years of age or older, and 19% were 75 years of age or older. No overall differences in safety or effectiveness were observed in patients 65-74 years of age compared to younger patients. Clinical studies did not include sufficient numbers of patients 75 years of age or older to determine whether they respond differently from younger patients.
Gender
There is no FDA guidance on the use of Elranatamab-bcmm with respect to specific gender populations.
Race
There is no FDA guidance on the use of Elranatamab-bcmm with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Elranatamab-bcmm in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Elranatamab-bcmm in patients with hepatic impairment.
Females of Reproductive Potential and Males
ELREXFIO may cause fetal harm when administered to a pregnant woman.
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating treatment with ELREXFIO.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of ELREXFIO.
Immunocompromised Patients
There is no FDA guidance one the use of Elranatamab-bcmm in patients who are immunocompromised.
Administration and Monitoring
Administration
2.6 Preparation and Administration Instructions ELREXFIO is intended for subcutaneous use by a healthcare provider only.
ELREXFIO should be administered by a healthcare provider with adequate medical personnel and appropriate medical equipment to manage severe reactions, including CRS and neurologic toxicity, including ICANS [see WARNINGS AND PRECAUTIONS (5.1, 5.2)].
ELREXFIO 76 mg/1.9 mL (40 mg/mL) vial and 44 mg/1.1 mL (40 mg/mL) vial are supplied as ready-to-use solution that do not need dilution prior to administration.
ELREXFIO is a clear to slightly opalescent, and colorless to pale brown liquid solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer if solution is discolored or contains particulate matter.
Use aseptic technique to prepare and administer ELREXFIO.
Preparation
ELREXFIO vials are for one-time use in a single patient and do not contain any preservatives.
Prepare ELREXFIO following the instructions below (see TABLE 7) depending on the required dose. Use a 44 mg/1.1 mL (40 mg/mL) single-dose vial for step-up dose 1 or step-up dose 2.
Monitoring
There is limited information regarding Elranatamab-bcmm Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Elranatamab-bcmm and IV administrations.
Overdosage
There is limited information regarding Elranatamab-bcmm overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Elranatamab-bcmm Pharmacology in the drug label.
Mechanism of Action
Elranatamab-bcmm is a bispecific B-cell maturation antigen (BCMA)-directed T-cell engaging antibody that binds BCMA on plasma cells, plasmablasts, and multiple myeloma cells and CD3 on T-cells leading to cytolysis of the BCMA-expressing cells. Elranatamab-bcmm activated T-cells, caused proinflammatory cytokine release, and resulted in multiple myeloma cell lysis.
Structure
Elranatamab-bcmm is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager. It is a bispecific, humanized immunoglobulin 2-alanine (IgG2Δa) kappa antibody derived from two monoclonal antibodies (mAbs), an anti-BCMA mAb and an anti-CD3 mAb. Each of these mAbs contributes one distinct heavy (H) chain and one distinct light (L) chain to the bispecific elranatamab-bcmm. The resulting 4-chain bispecific antibody is covalently linked via five inter-chain disulfide bonds. Elranatamab-bcmm is produced using two recombinant Chinese hamster ovary (CHO) cell lines, one that contains the DNA encoding the sequence for anti-BCMA monoclonal antibody (mAb) and one that contains the sequence for anti-CD3 mAb, which are grown separately in suspension culture using chemically-defined (CD), animal-derived component-free (ACF) media. The molecular weight of elranatamab-bcmm is approximately 148.5 kDa.
ELREXFIOTM (elranatamab-bcmm) injection is a sterile, preservative-free, clear to slightly opalescent, and colorless to pale brown liquid solution for subcutaneous administration. ELREXFIO (elranatamab-bcmm) is supplied at a concentration of 40 mg/mL in either 76 mg/1.9 mL or 44 mg/1.1 mL single-dose vials. Each mL of solution contains 40 mg elranatamab-bcmm, edetate disodium (0.045 mg), histidine (1.12 mg), L-histidine hydrochloride monohydrate (2.67 mg), polysorbate 80 (0.2 mg), sucrose (85 mg) and Water for Injection. The pH is 5.8.
Pharmacodynamics
Cytokine Concentrations
Transient elevation of circulating cytokines IL-2, IL-6, IL-8, IL-10, TNF-α, and IFN-γ was observed at dosage levels of 30 µg/kg (0.03 times the approved recommended dosage) and above. After administration of the approved recommended dosage of ELREXFIO, the highest elevation of cytokines was generally observed within 72 hours after first elranatamab-bcmm dose at 12 mg on Day 1, and generally returned to baseline before the administration of the first full dose 76 mg on Day 8.
Pharmacokinetics
Pharmacokinetic parameters are presented as geometric mean (coefficient of variation [CV]%) and are based upon subcutaneously administered unless otherwise specified.
Elranatamab-bcmm exhibits dose-proportional pharmacokinetics over a dose range from 6 to 76 mg (0.079 to 1 times the approved recommended dosage). Elranatamab-bcmm maximum concentration [33.6 mcg/mL (48%)] is achieved at the end of the weekly dosing regimen (i.e., at week 24 of 76 mg weekly dosing).
Absorption
The mean bioavailability of elranatamab-bcmm was 56.2% when administered subcutaneously. The median (min, max) Tmax after elranatamab SC administration was 7 (3 to 7) days.
Distribution
The steady state volume of distribution of elranatamab-bcmm was 7.76 L (33%).
Elimination
The half-life of elranatamab-bcmm is 22 (64%) days at the 76 mg dosage, with clearance of 0.324 L/day (100%) following 24 weeks dosing.
Metabolism
Elranatamab-bcmm is expected to be metabolized into small peptides by catabolic pathways.
Specific Populations
No clinically significant differences in the pharmacokinetics of elranatamab-bcmm were observed based on age (36 to 89 years), sex, race (White, Asian, or Black), body weight (37 to 160 kg), mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] by Modification of Diet in Renal Disease [MDRD] method: 30 to 89 mL/min), or mild hepatic impairment (total bilirubin 1 to ≤1.5 x ULN or any AST greater than ULN).
The effects of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR <15 mL/min), or moderate to severe hepatic impairment (total bilirubin >1.5 times ULN and any AST) on the PK of elranatamab-bcmm are unknown.
Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of elranatamab-bcmm or of other elranatamab products.
In the MagnetisMM-3 study, of the 168 participant who received recommended step-up and full dosage of ELREXFIO for up to 24 month and are evaluable for presence of ADA against elranatamab-bcmm, 8.9% (15/168) of patients tested positive for anti-elranatamab-bcmm-antibodies. Among the 15 patients who tested positive for ADAs, 60% (9/15) tested positive for neutralizing antibodies against elranatamab-bcmm. The effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of ELREXFIO products is unknown.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or genotoxicity studies have been conducted with elranatamab-bcmm.
No animal studies have been performed to evaluate the effects of elranatamab-bcmm on fertility.
Clinical Studies
Relapsed or Refractory Multiple Myeloma The efficacy of ELREXFIO monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in an open-label, single-arm, multi-center study (MagnetisMM-3, NCT04649359). The study included patients who were refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and one anti-CD38 monoclonal antibody. MagnetisMM-3 included 123 patients naïve to prior BCMA-directed therapy (pivotal Cohort A) and 64 patients with prior BCMA-directed antibody-drug conjugate (ADC) or chimeric antigen receptor (CAR) T-cell therapy (supportive Cohort B). Patients had measurable disease by International Myeloma Working Group (IMWG) criteria at enrollment. The study included patients with an Eastern Cooperative Oncology Group (ECOG) score of ≤2, adequate baseline bone marrow (absolute neutrophil count ≥1.0 x 109/L, platelet count ≥25 x 109/L, hemoglobin level ≥8 g/dL), renal (CrCL ≥ 30 mL/min), and hepatic (AST and ALT ≤2.5 x ULN, total bilirubin ≤2 x ULN) function, and left-ventricular ejection fraction ≥40%. Patients with a stem cell transplant within 12 weeks before enrollment and active infections were excluded from the study.
Eligible patients received subcutaneous administration of ELREXFIO at step-up doses of 12 mg on Day 1 and 32 mg on Day 4 of treatment, followed by the first treatment dose of ELREXFIO (76 mg) on Day 8 of treatment. Thereafter, patients received 76 mg once weekly. After 24 weeks, in patients who achieved an IMWG response category of partial response or better with responses persisting for at least 2 months, the dose interval was changed from every week to every 2 weeks.
The 123 patients enrolled in pivotal Cohort A had received a median of 5 prior lines of therapy (range: 2 to 22). Ninety-seven patients who were not exposed to prior BCMA-directed therapy and received at least four prior lines of therapy comprised the efficacy population. Among the 97 patients in the efficacy population, the median age was 69 (range: 46 to 89) years with 18.6% of patients ≥75 years of age. Forty percent were female; 59.8% were White, 13.4% were Asian, 7.2% were Hispanic/Latino, and 5.2% were Black or African American. Disease stage (R-ISS) at study entry was 20.6% in Stage I, 53.6% in Stage II, and 17.5% in Stage III. The median time from the initial diagnosis of multiple myeloma to enrollment was 79.6 (range: 16 to 228) months. 96.9% were triple-class refractory, and 94.8% were refractory to their last line of therapy. 69.1% received prior autologous stem cell transplantation, and 7.2% received prior allogeneic stem cell transplantation. High-risk cytogenetics [t(4;14), t(14;16), or del(17p)] were present in 22.7% of patients. 34.0% of patients had extramedullary disease at baseline by BICR.
Efficacy was based on response rate and duration of response (DOR), as assessed by BICR based on IMWG criteria. The median (range) time to first response (TTR) was 1.22 (0.9 to 6.5) months. With a median follow-up of 11.1 months (95% CI: 10.6, 12.0) among responders, the DOR rate at 6 months was 90.4% (95% CI: 78.4%, 95.9%) and at 9 months was 82.3% (95% CI: 67.1%, 90.9%).
Among the 64 patients enrolled in Cohort B who previously received a PI, an IMiD, an anti-CD38 monoclonal antibody, and a BCMA-directed therapy, 63 patients received at least four prior lines of therapy. Patients had received a median of 8 prior lines of therapy (range: 4 to 19); 73% and 32% received prior BCMA-directed ADC and CAR T-cell therapy, respectively.
Confirmed ORR by BICR was 33.3% (95% CI: 22.0, 46.3). After a median (95% CI) follow-up of 10.2 (9.9, 11.0) months among responders, median DOR was not reached (95% CI: NE, NE) and the DOR rate at 9 months was 84.3% (95% CI: 58.7, 94.7).
How Supplied
ELREXFIOTM (elranatamab-bcmm) injection is a sterile, preservative-free, clear to slightly opalescent, and colorless to pale brown liquid solution supplied as follows:
•One 76 mg/1.9 mL (40 mg/mL) single-dose vial in a carton. NDC: 0069-4494-02 •One 44 mg/1.1 mL (40 mg/mL) single-dose vial in a carton. NDC: 0069-2522-02 ELREXFIO is supplied in a single-dose glass vial sealed with a rubber stopper (not made of natural rubber latex) and an aluminum seal with a flip-off cap.
Storage
Store refrigerated at 2 °C to 8 °C (36 °F to 46 °F) in the original carton until time of use to protect from light.
Do not freeze or shake the vial or carton.
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Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Cytokine Release Syndrome (CRS)
Discuss the signs and symptoms associated with CRS, including fever, hypoxia, chills, hypotension, tachycardia, and elevated liver enzymes. Advise patients to immediately contact their healthcare provider if they experience any signs or symptoms of CRS. Advise patients that they will be hospitalized for 48 hours after administration of the first step-up dose, and for 24 hours after administration of the second step-up dose.
Neurologic Toxicity, Including Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS)
Discuss the signs and symptoms associated with neurologic toxicity, including ICANS, including headache, encephalopathy, motor dysfunction, sensory neuropathy, and Guillain-Barré Syndrome. Advise patients to immediately contact their healthcare provider if they experience any signs or symptoms of neurologic toxicity. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery for 48 hours after completing each of the 2 step-up doses and the first treatment dose within the ELREXFIO step-up dosing schedule and in the event of new onset of any neurological toxicity symptoms until symptoms resolve.
ELREXFIO REMS
ELREXFIO is available only through a restricted program called ELREXFIO REMS. Inform patients that they will be given an ELREXFIO Patient Wallet Card that they should carry with them at all times and show to all of their healthcare providers. This card describes signs and symptoms of CRS and neurologic toxicity, including ICANS which, if experienced, should prompt the patient to immediately seek medical attention.
Infections
Discuss the signs and symptoms of infection.
Neutropenia
Discuss the signs and symptoms associated with neutropenia and febrile neutropenia.
Hepatotoxicity
Advise patients that liver enzyme elevations may occur and that they should report symptoms that may indicate liver toxicity, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
Embryo-Fetal Toxicity
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant. Advise females of reproductive potential to use effective contraception during treatment with ELREXFIO and for 4 months after the last dose.
Lactation
Advise women not to breastfeed during treatment with ELREXFIO and for 4 months after the last dose.
Precautions with Alcohol
Alcohol-Elranatamab-bcmm interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
ELREXFIO
Look-Alike Drug Names
There is limited information regarding Elranatamab-bcmm Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.