Elranatamab 44mg/1.1ml solution for injection vials

Extramedullary disease (EMD) in multiple myeloma refers to soft-tissue plasmacytomas that spread hematogenously and grow independently of bone, an aggressive phenotype that has been associated with poorer responses and shorter survival across successive treatment eras. Bispecific antibodies are highly active in relapsed or refractory multiple myeloma (RRMM), but their efficacy in patients with baseline EMD has not been quantitatively synthesized. We performed a systematic review and meta-analysis, reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidance, of prospective trials of B-cell maturation antigen (BCMA)- or G protein-coupled receptor class C group 5 member D (GPRC5D)-directed CD3 bispecific antibodies in RRMM that reported the objective response rate (ORR) in patients with baseline EMD. One estimate per trial was included; proportions were pooled using a random-effects model on the logit scale with restricted maximum-likelihood estimation of between-study variance, and heterogeneity was assessed with the Cochran Q test and the I-squared statistic; fixed-effect and leave-one-out sensitivity analyses were performed, and risk of bias was appraised for each EMD subgroup. Four prospective studies comprising 144 patients with baseline EMD were included. Study-level ORRs were 58.3% for teclistamab, 38.5% for elranatamab, 52.6% for linvoseltamab, and 44.6% for talquetamab when recommended phase 2 dose cohorts were combined. The random-effects pooled ORR was 45.2% (95% CI, 37.2-53.4), with no observed between-study heterogeneity (I-squared = 0%); estimates were identical under a fixed-effect model, and leave-one-out pooled ORRs ranged narrowly from 44.0% to 47.6%. BCMA- and GPRC5D-directed bispecific antibodies produce objective responses in approximately half of patients with RRMM and baseline EMD, with broadly similar activity across agents despite high-risk biology, although the small number of trials and their differing, sometimes paramedullary-inclusive, definitions of EMD warrant caution in interpreting this estimate. These pooled estimates provide a benchmark for patient counseling and trial design and support combination strategies to improve outcomes in this population.

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Abstract Background: Bispecific antibodies (BsAbs) targeting BCMA (teclistamab, elranatamab) and GPRC5D (talquetamab) have transformed relapsed/refractory multiple myeloma (RRMM), achieving overall response rates (ORR) of 61–70% in heavily pretreated patients. However, standard weekly dosing is associated with grade ≥3 infections in 45–55% of recipients, driven by prolonged hypogammaglobulinemia and T‑cell exhaustion. Emerging evidence suggests that reducing dosing frequency to every 2 or 4 weeks after deep response may preserve efficacy while curbing infectious toxicity. Objective: To systematically evaluate whether reduced‑frequency dosing (Q2W or Q4W) of FDA‑approved BsAbs in RRMM maintains clinical efficacy compared with standard weekly dosing, and to quantify the associated reduction in infection‑related adverse events. Methods: A PRISMA‑guided systematic review was conducted. PubMed, Embase, Scopus, Cochrane CENTRAL, Web of Science, and major hematology conference proceedings (ASH, ASCO, EHA, SOHO; 2022–2026) were searched. Included were prospective trials, cohort studies, and post hoc analyses reporting reduced-frequency BSAb dosing in adults with RRMM. Primary efficacy outcomes were ORR, progression‑free survival (PFS), and response maintenance after dose reduction. Secondary outcomes were grade ≥3 infections, hypogammaglobulinemia, and treatment discontinuation. Risk of bias was assessed using the ROBINS-I and the Newcastle-Ottawa Scale. Narrative synthesis was performed due to heterogeneity. Results: Fourteen studies (three pivotal trials with de‑escalation cohorts, six real‑world studies, five sub‑analyses) comprising >1,200 patients were included. For teclistamab, transition from weekly to Q2W after ≥6 months of complete response (CR) preserved responses in 100% (37/37) of patients (MajesTEC‑1). Real-world data showed comparable median PFS between the weekly and reduced-frequency groups (9.1 vs 11.3 months; p=0.141), despite lower dose intensity. All-grade infections declined from 6.08 to 2.25 per patient-year with Q2W dosing. For elranatamab, Q4W maintenance after ≥6 cycles of Q2W maintained responses in 92.6% (25/27) of patients at 6 months, with grade 3–4 infections decreasing from 17.9% to 10.7% after Q4W transition (Pfizer, 2025). For talquetamab, the FDA-approved Q2W primary schedule (0.8 mg/kg) achieved an ORR of 71% and a median PFS of 11.2 months, with grade ≥3 infections at 21%, substantially lower than those observed with BCMA-targeted agents (Chari et al., 2025). Across all agents, no study reported loss of response attributable to dose de‑escalation, but selection bias limits causal inference. Conclusion: Reduced‑frequency dosing (Q2W or Q4W) of teclistamab, elranatamab, and talquetamab in RRMM patients who have achieved deep, sustained responses preserves efficacy while substantially lowering infection rates. These findings support regulatory approvals for biweekly and monthly maintenance schedules. However, the evidence remains derived from non-randomized, single-arm cohorts with a moderate risk of bias. Prospective randomized trials are urgently needed to define optimal de-escalation timing, patient selection biomarkers, and comparative value against fixed-duration CAR T therapy.

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Relapsed/refractory multiple myeloma (RRMM) remains a challenging condition with a need for more effective treatment options. There are ongoing clinical trials analyzing the effects of anti-B-cell maturation antigen (BCMA) bispecific antibodies (Abs) against RRMM with early, promising results. This study aims to systematically evaluate the safety and efficacy of anti-BCMA bispecific antibodies in patients with RRMM. PubMed, Embase, Web of Science, and the American Society of Hematology (ASH) website were searched for published evidence on the safety and efficacy of anti-BCMA bispecific Abs. Screening was performed using original clinical trials published in English, RRMM, and anti-BCMA-CD3 bispecific Abs as our inclusion criteria. Our search yielded a total of 2211 articles. After screening, we found 11 relevant clinical trials (five phase I, one phase I/II, two phase Ib, two phase II, one phase III). Across the trials, 910 patients with ages ranging from 32 to 82 years were analyzed. A majority of patients were exposed to and/or refractory to triple-class and penta-drugs (prior therapies ranged from 1 to 25). AMG-420, AMG-701, elranatamab, REGN5458, teclistamab (Tec), alnuctamab (ALNUC), and ABBV-383 are the seven anti-BCMA-CD3 bispecific Abs currently being assessed in clinical trials as monotherapy and in combination with immunomodulators/proteasome inhibitors against RRMM. Across the included trials, elranatamab demonstrated overall response rates (ORRs) of 61-64%, while teclistamab ranged from 40% to 78% depending on the regimen. ALNUC and ABBV-383 achieved ORRs of 51% and 57%, respectively. Among patients previously exposed to and/or refractory to anti-BCMA therapies (including antibody-drug conjugates and CAR-T cell therapy), ORRs were 54% for elranatamab and 40% for teclistamab. Incidence of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) was low with subcutaneous (SC) administration of tec, elranatamab, and ALNUC. Across the studies, no death was reported due to CRS, although it led to treatment discontinuation in one patient in AMG-420, two patients in AMG-701, and dose reduction in three patients in ABBV-383 trials. Our analysis of the trials revealed that bispecific Abs showed efficacy in RRMM, with CRS and hematologic toxicities being the most common adverse events, mostly low-grade and manageable. Based on the promising efficacy and safety of BCMA targeting bispecific Abs, these drugs are emerging as a new therapeutic option for patients with advanced and RRMM.

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