Dual Targeting of Extramedullary Myeloma with Talquetamab and Teclistamab

Author(s): Shaji Kumar, M.D.¹; María-Victoria Mateos, Ph.D.^2,3,4,5; Jing Christine Ye, M.D.⁶; Shebli Atrash, M.D.⁷; Hila Magen, M.D.⁸; Hang Quach, M.D.⁹; Michael P. Chu, M.D.¹⁰; Suzanne Trudel, M.D.¹¹; Joshua Richter, M.D.¹²; Paula Rodríguez-Otero, M.D., Ph.D.¹³; Hun Chuah, M.D., Ph.D.¹⁴; Moshe Gatt, M.D.¹⁵; Eva Medvedova, M.D.¹⁶; Shahzad Raza, M.D.¹⁷; Dok Hyun Yoon, M.D., Ph.D.¹⁸; Tadao Ishida, M.D., Ph.D.¹⁹; Jeffrey V. Matous, M.D.²⁰; Laura Rosiñol, M.D., Ph.D.²¹; Koichi Onodera, M.D., Ph.D.²²; Emma Scott, M.D.²³; Christoph Heuck, M.D.²³; Jenny Zhang, Ph.D.²³; Todd Henninger, Ph.D.²⁴; Lisa O’Rourke, M.S.²³; Payal Thakkar, M.S.²⁴; Mariacristina Festa, M.S.²⁵; Lin Huang, Ph.D.²³; Jiangxiu Zhou, Ph.D.²³; Mikihiro Takamoto, M.P.H.²⁶; Lixia Pei, Ph.D.²⁴; Jiashen Lu, Ph.D.²⁷; Nicholas Au, Pharm.D., Ph.D.²³; Maria Krevvata, Ph.D.²³; Saad Z. Usmani, M.D.²⁸; Yael C. Cohen, M.D.²⁹; the RedirecTT-1 Investigators Study Group*;

Source: DOI: 10.1056/NEJMoa2514752

Dr. Anjan Patel's Thoughts

This is a very impressive signal in a notoriously difficult population—seeing a 79% response rate and median progression-free survival (PFS) of 15.4 months in true extramedullary, triple-class–exposed myeloma is better than expected. Toxicity is real and management-intensive, but the depth and durability of response make this dual-bispecific approach feel like a meaningful advance.

BACKGROUND

Patients with plasmacytomas that are noncontiguous with bone marrow (true extramedullary myeloma) are high risk for disease progression or relapse. Phase 1 of the RedirecTT-1 study showed promising efficacy with dual-antigen targeting of myeloma with talquetamab (anti–G protein–coupled receptor family C group 5 member D) plus teclistamab (anti–B-cell maturation antigen) in patients with triple-class–exposed relapsed or refractory multiple myeloma, including those with true extramedullary myeloma.

METHODS

In this phase 2 study, we investigated talquetamab plus teclistamab exclusively in patients with drug-resistant, true extramedullary myeloma. The primary end point was overall response, evaluated with the use of functional imaging. Secondary end points included the duration of response, progression-free survival, overall survival, and safety.

RESULTS

A total of 90 patients were enrolled in the study and received treatment (median follow-up, 12.6 months). A response occurred in 79% of the patients (95% confidence interval [CI], 69 to 87). Among the patients with a response, the percentage with a response duration of least 12 months was 64% (95% CI, 48 to 76). 12 months, progression-free survival was 61% (95% CI, 50 to 71), and overall survival was 74% (95% CI, 63 to 83). Common adverse events of any grade included oral symptoms, such as dysgeusia, dry mouth, and dysphagia (in 87% of the patients); cytokine release syndrome (in 78%); and nonrash skin effects (in 69%). Grade 3 or 4 adverse events (most commonly hematologic events) occurred in 76% of the patients; 31% had grade 3 or 4 infection. A nonfatal adverse event led to discontinuation of one or both agents in 6% of the patients. Among 10 deaths that occurred during follow-up, 5 were due to infection and 5 were considered to be related to the study treatment.

CONCLUSIONS

Most patients with drug-resistant, true extramedullary myeloma had a response with talquetamab plus teclistamab. The incidence of adverse events of grade 3 or above was high and was consistent with previous observations for each agent as monotherapy. (Funded by Johnson & Johnson; RedirecTT-1 ClinicalTrials.gov number, NCT04586426.)

Author Affiliations

¹Mayo Clinic Rochester, Rochester, MN; ²University Hospital of Salamanca, Salamanca, Spain; ³Institute for Biomedical Research of Salamanca, Salamanca, Spain; ⁴The Salamanca Cancer Research Center, Salamanca, Spain; ⁵Centro de Investigacion Biomedica en Red Cancer, Salamanca, Spain; ⁶M.D. Anderson Cancer Center, University of Texas, Houston; ⁷Levine Cancer Institute–Atrium Health, Charlotte, NC; ⁸Chaim Sheba Medical Center, Ramat-Gan, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; ⁹University of Melbourne, St. Vincent’s Hospital, Melbourne, VIC, Australia; ¹⁰Alberta Health Services, Edmonton, Canada; ¹¹Princess Margaret Cancer Centre, Toronto; ¹²Mount Sinai Medical Center, New York; ¹³Cancer Center Clínica Universidad de Navarra, Cima, Pamplona, Spain; ¹⁴Royal Perth Hospital, Perth, WA, Australia; ¹⁵Hadassah Medical Cener, Hebrew University of Jerusalem, Jerusalem, Israel; ¹⁶Knight Cancer Institute, Oregon Health and Science University, Portland; ¹⁷Taussig Cancer Institute, Cleveland Clinic, Cleveland; ¹⁸Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; ¹⁹Japanese Red Cross Medical Center, Tokyo; ²⁰Colorado Blood Cancer Institute and Sarah Cannon Research Institute, Denver; ²¹Hospital Clínic de Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; ²²Tohoku University Hospital, Sendai-shi, Miyagi, Japan; ²³Johnson & Johnson, Spring House, PA; ²⁴Johnson & Johnson, Raritan, NJ; ²⁵Johnson & Johnson, Leiden, the Netherlands; ²⁶Johnson & Johnson, Tokyo; ²⁷Johnson & Johnson, Shanghai; ²⁸Memorial Sloan Kettering Cancer Center, New York; ²⁹Tel Aviv Sourasky (Ichilov) Medical Center, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel

Lisocabtagene Maraleucel Versus Standard of Care for Second-Line Relapsed/Refractory Large B-Cell Lymphoma: 3-Year Follow-Up From the Randomized, Phase III TRANSFORM Study

CAR-T therapy outperformed standard of care (SOC) as a second-line treatment, with progression-free survival (PFS) not reached in the CAR-T group compared to 6.2 months in the SOC group. Despite two-thirds of patients crossing over, CAR-T still demonstrated a three-year overall survival rate of 63%, versus 52% with SOC. These are impressive and durable results. The SOC regimen consisted of three cycles of chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant. This positions CAR-T as a viable second-line option for eligible patients.

Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study

Guess who’s coming as an option beyond AI (OBI)? Yes—this study showed no safety concerns and demonstrated comparable efficacy.

Measurable Residual Disease–Guided Therapy in Newly Diagnosed Myeloma

Quadruplet induction with isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa‑KRd) has reset expectations for transplant‑eligible NDMM and enables measurable residual disease (MRD)‑adapted strategies; MRD‑negativity at 10^-5 is strongly prognostic, and the necessity of autologous stem-cell transplantation (ASCT)—particularly tandem ASCT—amid deep responses is being re‑examined. Practically, MRD‑adapted consolidation after Isa‑KRd suggests no added depth from ASCT in MRD patients and no advantage for tandem ASCT over single ASCT + Isa‑KRd in MRD+ patients. So in day‑to‑day practice, this looks like a chance to de‑escalate transplant intensity while awaiting mature progression-free survival (PFS)/overall survival (OS) data.

Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma

The AQUILA trial compared daratumumab to active monitoring in high-risk smoldering multiple myeloma, demonstrating a significant improvement in progression-free survival (PFS) (84% vs 54% at 48 months) and a trend toward better overall survival (OS) (94% vs 86% at 48 months). Dara also achieved a higher rate of deep responses, with 60% of patients reaching minimal residual disease (MRD) negativity compared to none in the monitoring arm. This looks like a game-changer to delay progression, but we’ll need to weigh the toxicity profile carefully in practice and wait for survival data.

Salvage autologous transplant in relapsed multiple myeloma: long-term follow-up of the phase 3 GMMG ReLApsE trial

Is the need to transplant declining? Salvage autologous transplant vs lenalidomide/dexamethasone offers no significant survival benefit in RRMM. Patients who relapsed were treated with high-dose chemotherapy followed by maintenance lenalidomide vs dexamethasone and lenalidomide and progression-free survival (PFS) was 20 vs 19 months.