Talquetamab 40mg/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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T-cell-redirecting therapies have transformed the treatment of relapsed/refractory multiple myeloma (RRMM) but are associated with substantial infection risk. We systematically reviewed infections after CAR T-cell therapy and bispecific antibodies (BsAbs), focusing on incidence, timing, pathogens, risk factors, and prevention. Following PRISMA guidelines, we searched PubMed through May 22, 2026, and included studies reporting infectious outcomes in RRMM patients treated with CAR-T cells or BsAbs. A total of 123 predominantly early-phase, non-comparative studies were analyzed. Across BCMA-directed CAR-T products and BsAbs, infections were frequent (any-grade incidence ~ 40-80%), with highest risk early after CAR-T infusion and during the first months of BsAb therapy. Grade ≥ 3 infections were common and exceeded 50% in several BsAb cohorts. Fatal infections were less frequent but occurred across both CAR-T and BsAb studies. In randomized CAR-T trials, grade 5 infections represented a substantial proportion of treatment-related deaths. Talquetamab showed lower infection rates (47-55%) but relevant mucocutaneous toxicity. Viral and bacterial pathogens predominated; CMV reactivation, invasive fungal infections, and Pneumocystis jirovecii pneumonia, particularly without prophylaxis, were also reported. Risk factors included neutropenia, corticosteroid/tocilizumab exposure, and hypogammaglobulinemia. Antiviral and Pneumocystis jirovecii pneumonia (PJP) prophylaxis and, most notably, immunoglobulin replacement reduced infections, though residual risk persisted. Real-world data suggest higher infection-related healthcare use and mortality with BsAbs versus CAR-T therapy. Extended dosing intervals may reduce infections, particularly severe infections, while preserving efficacy. Infectious toxicity remains a key limitation. Risk is particularly high with BCMA-targeted therapies and continuous BsAb administration. Tailored prophylaxis, early immunoglobulin replacement, and response-adapted treatment strategies, including extended dosing intervals, may improve safety and outcomes.

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