ELREXFIO Solution for injection Ref.[107409] Active ingredients: Elranatamab

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.

Table 10. Pharmacokinetic Parameters of Elranatamab-bcmm in Subjects with Relapsed or Refractory Multiple Myeloma:

^* In patients who have achieved a response.
^† Steady state exposure of elranatamab biweekly dose is approximated at week 48.

Absorption

The mean bioavailability of elranatamab-bcmm was 56.2% when administered subcutaneously. The median (min, max) T_max 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.

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.

14.1 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 × 10⁹/L, platelet count ≥25 × 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 prior to 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, 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 since 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 allogenic 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. Efficacy results from BCMA-directed therapy naïve patients are shown in Table 11.

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%).

Table 11. Efficacy Results from BCMA-directed Therapy Naïve Patients:

Abbreviations: CI = Confidence interval; NR = Not reached; NE = Not estimable.
^* Complete response or better = Stringent complete response (sCR) + complete response (CR).

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).