Background: Teclistamab, a BCMA×CD3 bispecific T-cell engager, offers an off-the-shelf immunotherapy option for relapsed/refractory multiple myeloma (RRMM). Despite pivotal trial efficacy, real-world outcomes in elderly, comorbid, and geographically isolated patients—underrepresented in MajesTEC-1—are poorly characterized. The Midwest is a high-priority region for study: 46% of residents live in rural areas (vs. 14% nationally), 78% of counties lack clinical trial infrastructure, and patients frequently travel >90 miles for care. This multicenter analysis evaluates real-world effectiveness, safety, and dosing adaptations of teclistamab in Midwest RRMM population, across four high-volume academic centers (Indiana University, the Ohio State University, Penn State University, and University of Wisconsin) serving large rural referral bases in the Midwest.

Methods: This multicenter retrospective cohort study included 159 RRMM patients treated with teclistamab as a standard of care across four institutions from October 2022 to March 2025. All patients underwent inpatient step-up dosing and transitioned to outpatient maintenance. Demographics, treatment history (prior BCMA exposure, organ dysfunction), response (IMWG), progression (TTP), overall survival (OS), and toxicity were collected. Dose de-escalation patterns (weekly → biweekly/monthly) and off-therapy were analyzed. Kaplan-Meier curves, log-rank tests, and multivariable Cox models were used for outcome analysis.

Results: Patient Characteristics: Median age was 73 years (range 38–88; 62% ≥75 years), with 45% having baseline organ dysfunction and 58% triple-class refractory disease. Prior BCMA-directed therapy was common (38%: 24% CAR-T/BiTE, 14% ADC).

Efficacy: Overall response rate (ORR) was 63% (VGPR+: 42%; CR/unconfirmed CR: 21%). The median TTP for the entire cohort was 8.2 months (95% CI 6.1–10.3). A bimodal survival pattern emerged: Non-responders (37%, *n*=59) had rapid disease progression, with a median TTP of 2.1 months (95% CI 1.5–3.0) and accounted for 82% of deaths within 6 months. Responders (63%, *n*=100) demonstrated sustained disease control, with a median TTP of 15.8 months (95% CI 12.4–18.9). Patients responding by 3 months (early responders, 89% of ORR) had 12-month progression-free rate: 68%, while patients not responding by 3 months (late progressors, 11%) had median TTP of 4.3 months (95% CI 3.1–5.8) and 12-month OS was only 21%. TTP was significantly shorter in patients with prior CAR-T/BiTE exposure vs. BCMA-naïve (HR 2.1, *p*=0.003) but not prior ADC (*p*=0.27). Organ dysfunction did not impact TTP (HR 1.1, *p*=0.42).

Safety: CRS occurred in 51% (≥G3: 4%), ICANS in 18% (≥G3: 2%), and grade ≥3 infections in 29% (5% fatal). Infection-related mortality was linked to fragmented care transitions (30% referred to community sites post-initiation) and delayed IVIG access (median 21 days from hypogammaglobulinemia).

Dosing Heterogeneity & Outcomes: Dose reduction occurred at a median of 14 weeks (interquartile range: 12–18 weeks). Among the 108 patients (68% of the cohort) who underwent dose reduction, a majority (58%, *n*=63) reduced intensity upon achieving ≥VGPR, typically by Cycle 2–3 (median 10 weeks), with 92% maintaining progression-free survival at 12 months. Another 27% (*n*=29) reduced dosing due to adverse events (AEs), primarily infections, at a median of 16 weeks; this group had a 12-month PFS of 76%. The remaining 15% (*n*=16) had unclear cause for reduced frequency, with 81% remaining progression-free. Notably, 22% of AE-driven reductions occurred concurrently with deep responses (VGPR+), blurring the distinction between toxicity-driven and response-adapted decisions. Among responders who continued weekly dosing beyond 12 weeks (32%, *n*=32), 68% developed new or worsening infections, and 44% required unplanned reductions later in treatment.

Conclusion: Teclistamab demonstrates robust efficacy and manageable safety in real-world RRMM, including patients traditionally excluded from trials due to age, comorbidities, and rural residence. Short overall TTP reflects aggressive early progression in high-risk subgroups; responders exhibit durable benefit with many remaining on extended or no therapy past 12 months. Response-adapted dosing (biweekly/monthly) optimizes adherence and safety without compromising efficacy—a critical strategy for rural patients. Prior CAR-T/BiTE (not ADC) significantly impairs outcomes, informing therapy sequencing.

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2025
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