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.
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 prior to the administration of the first full dose 76 mg on Day 8.
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 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 weekly dosing regimen (i.e., at week 24 of 76 mg weekly dosing). Pharmacokinetic exposures are summarized for the recommended dosage of ELREXFIO in Table 10.
Timepoint | Parameters | ||
Cavg (mcg/mL) | Cmax (mcg/mL) | Ctrough (mcg/mL) | |
First full 76 mg dose | 3.1 (94%) | 3.8 (94%) | 3.3 (102%) |
End of weekly dose (week 24)* | 32.7 (49%) | 33.6 (48%) | 31.2 (50%) |
18.4 (57%) | 20.1 (55%) | 15.9 (64%) | |
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.
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.
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.
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 prior to the administration of the first full dose 76 mg on Day 8.
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 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 weekly dosing regimen (i.e., at week 24 of 76 mg weekly dosing). Pharmacokinetic exposures are summarized for the recommended dosage of ELREXFIO in Table 10.
Timepoint | Parameters | ||
Cavg (mcg/mL) | Cmax (mcg/mL) | Ctrough (mcg/mL) | |
First full 76 mg dose | 3.1 (94%) | 3.8 (94%) | 3.3 (102%) |
End of weekly dose (week 24)* | 32.7 (49%) | 33.6 (48%) | 31.2 (50%) |
18.4 (57%) | 20.1 (55%) | 15.9 (64%) | |
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.
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.
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