Editor's Note: From June 12 to 15, 2025, the European Hematology Association (EHA) Annual Congress was held in Milan, Italy, bringing together top experts in the field of hematology from around the globe. In the highly anticipated Late-Breaking Abstract session, Professor Shaji Kumar from the Mayo Clinic, on behalf of his collaborative research team, announced pivotal data from the Phase II cohort of the Redirectt-1 study on Talquetamab combined with Teclistamab for the treatment of patients with Relapsed/Refractory Multiple Myeloma (RRMM) and Extramedullary Disease (EMD). This research offers unprecedented therapeutic hope for this patient subgroup with an extremely poor prognosis and has the potential to change the landscape of clinical practice.Extramedullary Disease: The “Solid Ice” of Multiple Myeloma Treatment
Multiple myeloma is a hematologic malignancy characterized by the abnormal proliferation of plasma cells in the bone marrow. However, when these malignant plasma cells break through the confines of the bone and form tumors in soft tissues or organs outside the bone marrow, it is known as Extramedullary Disease (EMD). At the beginning of his presentation, Professor Kumar emphasized that EMD is a highly aggressive subtype of multiple myeloma, associated with a very poor prognosis whether detected at initial diagnosis or at relapse.
He cited a meta-regression analysis indicating that patients with EMD are 87% less likely to respond to treatment compared to those without EMD. Furthermore, real-world study data shows that EMD patients have significantly lower response rates, and their Progression-Free Survival (PFS) and Overall Survival (OS) are nearly half those of non-EMD patients. These data highlight the significant unmet clinical need in the EMD patient population, as existing therapies have struggled to break this “solid ice.”
A Dual-Pronged Approach: The Innovative Design and Rationale of the Redirectt-1 Study
Facing the therapeutic challenges of EMD, the Redirectt-1 study proposed an innovative “dual-target” combination strategy. The study combines two first-in-class T-cell redirecting bispecific antibodies: Talquetamab, which targets G protein-coupled receptor class 5 member D (GPRC5D), and Teclistamab, which targets B-cell Maturation Antigen (BCMA). Both drugs have been approved as monotherapies for the treatment of RRMM patients.
Professor Kumar explained that EMD is biologically complex, with heterogeneity in genetic features and antigen expression, which may be why existing therapies fail. By simultaneously targeting two different tumor surface antigens, GPRC5D and BCMA, the research team hypothesized that they could more effectively activate T-cells, overcome tumor escape mechanisms, and thereby produce a more potent and durable cytotoxic effect against EMD.
This Phase II study specifically enrolled RRMM patients with at least one EMD lesion greater than 2 cm, confirmed by rigorous central imaging review, who had been exposed to the “triple class” of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. Notably, the study also included nearly 38% of patients with oligosecretory or non-secretory disease, who are often excluded from clinical trials due to a lack of traditional serological markers, demonstrating the study’s focus on real-world complex cases.
Stunning Data: Unprecedented Depth of Response and Durable Survival
With a median follow-up of 12.6 months, the combination of Talquetamab and Teclistamab achieved remarkable efficacy. The Overall Response Rate (ORR) for this regimen was an impressive 80%, far exceeding the historical data of approximately 43% for either monotherapy in EMD patients. More importantly, the study achieved a very high depth of response, with 55% of patients achieving a Complete Response (CR), a figure that is more than three times the CR rate of monotherapy (around 15-18%).
The survival curves presented by Professor Kumar were equally encouraging. The median Progression-Free Survival (PFS) for this treatment regimen reached 15.4 months, with a one-year PFS rate of 61%. The one-year Overall Survival (OS) rate was 75%. Professor Kumar stressed that in the challenging field of EMD, no prior therapy, whether traditional chemotherapy or other novel immunotherapies, has ever demonstrated a PFS exceeding one year, making the results of the Redirectt-1 study a historic breakthrough. Furthermore, responses were durable, with a median Duration of Response (DOR) of 13.8 months, and at the time of data cutoff, two-thirds of responders were still on treatment.
Manageable Safety: Combination Therapy Did Not Increase Additional Toxicity
In terms of safety, the toxicity profile of the combination regimen was largely consistent with the known safety information of the two drugs when used alone, with no new or unexpected safety signals emerging. The incidence of Cytokine Release Syndrome (CRS) was 78%, with the vast majority being Grade 1 or 2 and occurring primarily during the step-up dosing phase. The incidence of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) was 12%, also predominantly low-grade. Infections were an adverse event of interest, reported in nearly 80% of patients, but the proportion of Grade 3-4 severe infections was about one-third, which may be related to the flexible dosing schedule (allowing a switch to monthly dosing after 4-6 cycles) potentially reducing infection risk. Overall, the safety profile of this regimen is predictable and manageable.
Expert Q&A: Clinical Practice Considerations and Future Outlook
During the Q&A session, several internationally renowned experts raised insightful questions about the clinical implications of the study results. Regarding the role of radiotherapy in EMD treatment, Professor Kumar opined that while radiotherapy is not suitable as a primary treatment for systemic EMD, its potential to clear residual lesions or enhance immunotherapy effects through an “abscopal effect” warrants further exploration in prospective studies.
When asked if this regimen should become the new standard of care for EMD patients, Professor Tom Martin from the University of California, San Francisco (UCSF) received an affirmative response from Professor Kumar. Professor Kumar stated that based on the current compelling data, he would prioritize this combination therapy for EMD patients if available, even over CAR-T cell therapy, due to its demonstration of better response durability.
In conclusion, Professor Kumar summarized that the Redirectt-1 study confirms that the combination of Talquetamab and Teclistamab is an “off-the-shelf” dual-targeting immunotherapy that brings unprecedented deep and durable responses to patients with extramedullary disease, an extremely difficult-to-treat subtype of multiple myeloma. This major advancement not only provides clinicians with a powerful new weapon but also has the potential to fundamentally change the natural history of EMD, bringing new hope to patients worldwide.
