Talquetamab/Teclistamab Combo Yields Responses With Increased Infection Incidence in Triple Class–Exposed Myeloma

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Treatment with the combination of talquetamab-tgvs (Talvey) and teclistamab-cqyv (Tecvayli) led to responses in patients with relapsed/refractory multiple myeloma who were previously exposed to a proteasome inhibitor (PI), an immunomodulatory drug (iMID), and an anti-CD38 monoclonal antibody. However, the regimen produced a higher level of grade 3/4 infections compared with rates associated with either bispecific antibody alone, according to data from the phase 1b/2 RedirecTT-1 trial (NCT04586426).1

Findings published in The New England Journal of Medicine showed that at a median follow-up of 20.3 months (range, 0.5-37.1), evaluable patients treated across all dose levels (n = 94) achieved an overall response rate (ORR) of 78%, including a complete response (CR) or better rate of 48% and a very good partial response (VGPR) or better rate of 74%. Among patients with extramedullary disease (n = 34), the ORR was 59%.

At a median follow-up of 18.2 months (range, 0.7-27.0) for patients (n = 44) treated the recommended phase 2 regimen (RP2R) of talquetamab at 0.8 mg/kg and teclistamab at 3.0 mg/kg once every 2 weeks, the ORR was 80%, including a CR or better rate of 52% and a VGPR or better rate of 77%. The ORR for patients with extramedullary disease (n = 18) was 61%.

Regarding safety, dose-limiting toxicities (DLTs) occurred in 1 patient treated with talquetamab at 0.2 mg/kg plus teclistamab at 0.75 mg/kg once per week (grade 3 oral herpes); 1 patient given talquetamab at 0.4 mg/kg plus teclistamab at 1.5 mg/kg once per week (grade 3 elevated alanine aminotransferase and aspartate aminotransferase levels); and 1 patient treated with the RP2R (grade 4 thrombocytopenia).

Across all dose levels, any-grade infections occurred in 89% of patients, and 64% experienced grade 3/4 infections. The incidence of first onset of grade 3 or higher infection was higher during the first 6 months of treatment vs other time periods. Additionally, 82% and 49% of patients received antiviral prophylaxis and Pneumocystis jirovecii pneumonia prophylaxis, respectively. Eleven percent of patients had opportunistic infections.

Sixty-three percent of patients received a COVID-19 vaccine. Forty percent of patients had any-grade COVID-19, including 18% with grade 3/4 COVID-19 and 2% of patients with a grade 5 event.

“Talquetamab plus teclistamab had a similar safety profile to each agent as monotherapy, although the observed incidence of grade 3 or 4 infections was higher with the combination than with talquetamab or teclistamab as monotherapies,” lead study author Yael C. Cohen, MD, of Tel Aviv Sourasky Medical Center in Israel, and colleagues wrote in a publication of the data. “Responses were observed across dose levels and were particularly deep and durable with the RP2R. On the basis of these results, this dual-targeting, off-the-shelf combination therapy warrants further investigation in patients with relapsed/refractory multiple myeloma.”

In October 2022, the FDA granted accelerated approval to teclistamab for adult patients with relapsed/refractory multiple myeloma who have received at least 4 previous lines of therapy, including a PI, an iMID, and an anti-CD38 monoclonal antibody.2 The regulatory agency gave accelerated approval to talquetamab in the same indication in August 2023.3

RedirecTT-1 Design

RedirecTT-1 was a multicenter, nonrandomized, open-label study that enrolled patients from Canada, Israel, South Korea, and Spain with measurable relapsed/refractory multiple myeloma with prior exposure to a PI, an iMID, and an anti-CD38 monoclonal antibody.1 Patients were required to have an ECOG performance status of 0 or 1. Those with extramedullary disease with at least 1 nonradiated, bone-independent lesion of at least 2 cm in the greatest dimension were allowed to participate.

Patients received treatment with the combination at 1 of 5 dose levels: 0.2 mg/kg of talquetamab plus 0.75 mg/kg of teclistamab once per week (dose level 1); 0.2 mg/kg of talquetamab plus 1.5 mg/kg of teclistamab once per week (dose level 2); 0.4 mg/kg of talquetamab plus 1.5 mg/kg of teclistamab once per week (dose level 3); 0.8 mg/kg of talquetamab plus 1.5 mg/kg of teclistamab once every 2 weeks (dose level 4); and the RP2R of 0.8 mg/kg of talquetamab plus 3.0 mg/kg of teclistamab once every 2 weeks (dose level 5). Treatment started with step-up dosing to mitigate severe cytokine release syndrome (CRS); step-up doses were administered 2 to 4 days apart and before full treatment doses.

The incidence of DLTs was the primary end point in phase 1. Secondary end points included ORR, duration of response (DOR), time to response, pharmacokinetics, pharmacodynamics, and immunogenicity.

In the overall population, the median age was 64.5 years (range, 39-81), 52% of patients were male, 80% were White, and 64% had an ECOG performance status of 1. Twenty-one percent of patients had bone marrow plasma cell levels above 60%, 36% of patients had at least 1 extramedullary plasmacytoma, and 41% had high-risk cytogenetics.

Disease stages included I (45%), II (31%), and III (25%). The median time since diagnosis was 6.1 years (range, 0.3-14.6), and patients received a median of 4 prior lines of therapy (range, 1-11). Seventy-nine percent of patients underwent an autologous stem cell transplant. Along with all patients being triple class exposed, 65% were penta drug exposed, 19% received prior treatment with belantamab mafodotin (Blenrep), 7% received a prior bispecific antibody, and 4% had prior CAR T-cell therapy. The rates of triple class–refractory and penta drug–refractory disease were 86% and 33%, respectively.

Additional Efficacy and Safety Data

Further data from the overall population found that the estimated 12- and 18-month DOR rates were 86% (95% CI, 75%-92%) and 77% (95% CI, 64%-85%), respectively. At the RP2R, these respective rates were 91% (95% CI, 75%-97%) and 86% (95% CI, 66%-95%).

In patients with extramedullary disease, the estimated 12- and 18-month DOR rates were 70% (95% CI, 45%-85%) and 52% (95% CI, 25%-74%), respectively. At the RP2R, these respective rates were both 82% (95% CI, 45%-95%).

Patients treated with the RP2R experienced an estimated 12-month progression-free survival (PFS) rate of 74% (95% CI, 57%-84%) and an estimated 18-month PFS rate of 70% (95% CI, 52%-82%). The PFS rate at both time points was 53% (95% CI, 28%-73%) for those with extramedullary disease. The 12-and 18-month PFS rates in the overall population were 71% (95% CI, 60%-79%) and 62% (95% CI, 51%-72%), respectively.

Any-grade CRS occurred in 79% of patients, and 2% had grade 3 CRS. Most instances of CRS were reported during step-up dosing and in early treatment cycles. The median time to onset and duration of CRS were both 2 days. CRS led to dose delays or modifications in 15% of patients. The rates of CRS recovery, CRS recovery with sequelae, and incomplete CRS recovery were 98%, 1%, and 1%, respectively.

Immune effector cell–associated neurotoxicity syndrome (ICANS) was reported in 3% of patients, including 1 instance of grade 3 ICANs. One patient experienced 2 ICANS events. All instances of ICANS events occurred during step-up dosing at a median time to onset of 2.5 days. The median duration of ICANS was 3 days, and all patients had recovered.

At all dose levels, grade 3/4 adverse effects (AEs) occurred in 96% of patients, with the most common including CRS, neutropenia, taste changes, and non-rash skin toxicity. AEs led to dose delays or modifications in 93% of patients, primarily attributable to infections (68%). AEs led to treatment discontinuation of 1 or both agents in 16% of patients, including 7% who discontinued due to treatment-related AEs.

AEs led to death in 15% of patients, of which 11 grade 5 AEs were infections.

“Prophylactic infection measures were recommended and administered according to institutional guidelines, but the proportion of patients receiving infection prophylaxis may have differed among the dose cohorts given that enrollment commenced at different time points and infection-management guidelines evolved during the conduct of the study,” study authors noted.

References

1. Cohen YC, Magen H, Gatt M, et al. Talquetamab plus teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2025;392(2):138-149. doi:10.1056/NEJMoa2406536
2. FDA approves teclistimab-cqyv for relapsed or refractory multiple myeloma. News release. FDA. October 25, 2022. Accessed May 22, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma
3. U.S. FDA approves Talvey (talquetamab-tgvs), a first-in-class bispecific therapy for the treatment of patients with heavily pretreated multiple myeloma. News release. Janssen. August 10, 2023. Accessed May 22, 2025. https://www.janssen.com/us-fda-approves-talveytm-talquetamab-tgvs-first-class-bispecific-therapy-treatment-patients-heavily