Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Regeneron Ireland DAC., One Warrington Place, Dublin 2, D02 HH27, Ireland
Pharmacotherapeutic group: Antineoplastic agents, Monoclonal antibodies and antibody drug conjugates
ATC code: not yet assigned
Linvoseltamab is a human IgG4-based bispecific antibody that binds to cluster of differentiation 3 (CD3), a T-cell antigen associated with the T-cell receptor complex, and B-cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. Simultaneous engagement of both arms of linvoseltamab results in formation of a synapse between the T-cell and the BCMA-expressing cell, resulting in T-cell activation and generation of polyclonal cytotoxic T-cell response, which result in redirected lysis of the targeted cells, including malignant multiple myeloma B-lineage cells. This effect occurs without regard to T-cell receptor specificity or reliance on major histocompatibility complex (MHC) Class I molecules on the surface of antigen-presenting cells.
Transient elevation of circulating cytokines (IL-2, IL-6, and IFN-γ) was primarily observed during the step-up dose regimen and the first full 200 mg dose. The highest elevation of cytokines was generally observed 4 hours after each infusion and generally returned to baseline prior to the next dose. Limited cytokine release was observed following subsequent doses (see section 4.4).
During treatment in LINKER-MM1 (evaluated through 30 months), the overall incidence of treatment-emergent anti-linvoseltamab antibodies was 1.0% (2/192) in patients treated with linvoseltamab. No evidence of anti-drug antibody impact on pharmacokinetics or safety was observed; however, data are still limited.
The efficacy of linvoseltamab was evaluated in patients with relapsed or refractory multiple myeloma in an open-label, multi-centre, multi-cohort, Phase ½ study: Study LINKER-MM1. The study included patients who had previously received at least 3 prior therapies, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 antibody.
The study excluded patients with known multiple myeloma brain lesions or meningeal involvement, history of a neurodegenerative condition, CNS movement disorder, history of a seizure within 12 months prior to study enrolment, any infection requiring hospitalisation or IV anti-infectives within 2 weeks of first administration of study drug, uncontrolled infection with HIV or HBV, a history of an allogeneic stem cell transplantation at any time, or autologous stem cell transplantation within 12 weeks of the start of study treatment, plasma cell leukaemia, primary systemic light-chain amyloidosis, Waldenstrom macroglobulinaemia, POEMS syndrome, and patients with an Eastern Cooperative Oncology Group performance score (ECOG PS) ≥ 2. Patients treated with prior BCMA-directed bispecific antibodies, bispecific T-cell engaging therapies, and BCMA CAR T cells were excluded. Patients could have received a BCMA antibody-drug conjugate.
All patients in both the Phase 1 and Phase 2 portions of the study received a single step-up treatment dose of 5 mg during week 1 and 25 mg during week 2 of LYNOZYFIC by IV infusion. After step-up dosing, patients received 200 mg of LYNOZYFIC weekly for 14 weeks in the Phase 1 portion of the study and 12 weeks for the Phase 2 portion of the study. Patients then received 200 mg every other week thereafter. After at least 24 weeks, the Phase 2 patients who achieved a VGPR or greater received 200 mg of LYNOZYFIC every 4 weeks. Patients were treated until disease progression or unacceptable toxicity. Patients in the study could receive tocilizumab and corticosteroids for the treatment of CRS.
The efficacy population included 12 patients from the Phase 1 and 105 patients from the Phase 2 portions of the study who received the recommended dose of LYNOZYFIC.
The median age was 70 (range: 37 to 91) years with 26% of patients 75 years or older; 55% were male and 45% were female; 71% were White, 17% were Black or African American, and 9% were Asian.
The International Staging System (ISS) for multiple myeloma at study entry was Stage I in 42%, Stage II in 35%, and Stage III in 18%. High-risk cytogenetics (presence of del(17p), t(4;14) and t(14;16)) were present in 39% of patients. Sixteen percent of patients had extramedullary plasmacytomas and 21% had paramedullary plasmacytomas. Twenty percent of patients had bone marrow plasma cell percentage ≥ 60%.
The median number of prior lines of therapy was 5 (range: 2 to 16); 97% of patients received at least 3 prior lines of therapy. Sixty-six percent of patients received prior stem cell transplantation. All patients received prior therapy with a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Eighty-two percent of patients were triple-class refractory (refractory to a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody). Nine percent of patients were previously treated with a BCMA antibody-drug conjugate. Eighty-five percent of patients were refractory to last line of therapy.
Efficacy was assessed based on objective response rate (ORR) as determined by blinded independent review committee (IRC), as measured using the international myeloma working group (IMWG) criteria. Secondary endpoints included duration of response (DOR) and rate of minimal residual disease (MRD) negative status. Data are shown in Table 9. The median (range) follow-up from initial dose for responders was 16 (2.5, 38) months.
In the Phase 2 portion of the study, 97% of responders on treatment after at least 12 months had transitioned to every 4-week dosing.
The median time to complete response (CR) or better was 8 months (range: 2, 14 months).
Table 9. Efficacy results for LINKER-MM1:
| Efficacy endpoints | LYNOZYFIC N=117 |
|---|---|
| Objective response rate (ORR) % (n) (95% CI) | 71% (83) (62, 79) |
| Complete response (CR) or better, % (n) (95% CI) | 50% (58) (40, 59) |
| Stringent complete response (sCR), % (n) | 44% (52) |
| Complete response (CR), % (n) | 5% (6) |
| Very good partial response (VGPR), % (n) | 14% (16) |
| Partial response (PR), % (n) | 8% (9) |
| Duration of response (DOR)a | N=83 |
| Median, months (95% CI) | 29 (19, NE) |
| Time to first response (months) | N=83 |
| Median, months (Range) | 0.95 (0.5, 6) |
| MRD negativity rate in patients achieving CR or sCR, % (n) [N=58]b (95% CI) | 41% (24) (29, 55) |
a DOR was defined as the time from the initial occurrence of a documented PR or CR until the patient experienced an event (documented disease progression or death due to any cause, whichever occurred first).
b MRD negativity was defined as the proportion of patients in CR or sCR who test MRD negative. MRD negativity was assessed using a next-generation sequencing assay (ClonoSEQ) based on a threshold of 10-5 or the Euroflow assay using a threshold of 10-5.
CI=confidence interval; MRD=minimal residual disease; NE=not estimable
The European Medicines Agency has waived the obligation to submit the results of studies with LYNOZYFIC in all subsets of the paediatric population for the treatment of multiple myeloma (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Pharmacokinetics of linvoseltamab was characterized in patients with relapsed or refractory multiple myeloma over a dose range of 1 mg to 800 mg following intravenous infusion. The Cmax, Ctrough, and AUCτ of linvoseltamab at the end of weekly, every other week dosing regimens and at steady state on every 4 week dosing regimen are presented at the 200 mg dose level in Table 10.
Table 10. Geometric mean (CV%) of model-based exposure parameters of recommended dose for linvoseltamab:
| Dosing period | Cmax (mg/L) | Ctrough (mg/L) | AUCτa (mg*day/L) |
|---|---|---|---|
| End of 200 mg weekly dose (Week 14) | 124 (50.4) | 61.8 (123) | 592 (74.6) |
| End of 200 mg every other week dose (Week 24) | 97.9 (52.7) | 30.2 (213) | 727 (95.3) |
| End of 200 mg every 4 weeks dose (Week 48) | 64.8 (45.1) | 6.3 (362) | 574 (84.6) |
a AUCτ for the specified dosing interval.
Based on the population pharmacokinetic model, the estimated geometric mean (CV%) of volume of distribution at steady-state (Vdss) of linvoseltamab is 7.05 L (33.6%).
Linvoseltamab is expected to be metabolized into small peptides by catabolic pathways.
The elimination of linvoseltamab is mediated by two parallel processes, a linear, non-saturable catabolic process, and a nonlinear, saturable target-mediated pathway.
Based on the population pharmacokinetic model, the time to reach lower limit of quantification (LLOQ) (0.078 mg/L) following the last dose of 200 mg weekly, every other week, and every 4 weeks is presented in Table 11.
Table 11. Elimination of recommended dose for linvoseltamab:
| Dosing period | Time to reach LLOQ (0.078 mg/L)a (Weeks) |
|---|---|
| 200 mg weekly | 20.1 [5.86, 40.3] |
| 200 mg every other week | 18.9 [5.43, 40.3] |
| 200 mg every 4 weeks | 15.6 [5.15, 36.4] |
a Values are median [5th and 95th percentile]
Results of population pharmacokinetic analyses indicate no clinically relevant differences in exposure (such as Ctrough, AUCτ) to linvoseltamab based on age (37 to 91 years; N=282), sex, and race [White (N=205), Asian (N=18), or Black (N=44)].
No formal studies of linvoseltamab in patients with renal impairment have been conducted.
Results of population pharmacokinetic analyses indicate no clinically relevant differences in exposure to linvoseltamab between patients with normal renal function (N=78; CrCL ≥ 90 mL/min) and with mild (N=116; CrCL ≥ 60 to < 90 mL/min), moderate (N=76; CrCL ≥ 30 to < 60 mL/min), and severe (N=11; CrCL ≥ 15 to < 30 mL/min) renal impairment.
No formal studies of linvoseltamab in patients with hepatic impairment have been conducted.
Results of population pharmacokinetic analyses indicate no clinically relevant differences in exposure to linvoseltamab between patients with normal (N=255) and with mild hepatic function (N=27; total bilirubin > ULN to 1.5 × ULN or AST > ULN). The effects of moderate (total bilirubin > 1.5 to 3 × ULN, any AST) and severe (total bilirubin > 3 to 10 × ULN, any AST) hepatic impairment on the PK of linvoseltamab are unknown.
No carcinogenicity or genotoxicity studies have been conducted with linvoseltamab.
No specific studies have been conducted to evaluate potential effects of linvoseltamab on fertility.
No developmental toxicity studies in animals have been conducted with linvoseltamab. Human IgG is known to cross the placenta; therefore, linvoseltamab has the potential to be transmitted from the mother to the developing foetus. Based on its mechanism of action, linvoseltamab may cause foetal B-cell and plasma cell lymphocytopenia that may be harmful to the foetus and transient CRS that may be harmful to pregnancy maintenance.
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