Editor's Note: The 29th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO) was held in Jinan from September 16 to 19, 2026, bringing together oncology experts from around the world to explore innovative approaches to precision diagnosis and treatment. During the multiple myeloma session, Professor Aijun Liu of Beijing Chao-Yang Hospital, Capital Medical University, presented an update on a phase II clinical study of eprenetapopt combined with bispecific antibodies in relapsed/refractory multiple myeloma (RRMM). In an interview with Oncology Frontier – Hematology Frontier, Professor Liu discussed the rationale behind the study design, the underlying mechanisms, the efficacy and safety profile of the combination, and directions for future research. The interview is presented below.Oncology Frontier – Hematology Frontier: At the CSCO multiple myeloma session, you will present an update on the phase II clinical study of eprenetapopt combined with bispecific antibodies in RRMM. What is the central rationale behind the study design, and what is the mechanistic basis for combining eprenetapopt with bispecific antibodies?
Professor Aijun Liu: The idea for this study originated from a particularly challenging case encountered in clinical practice. The patient had not previously received either eprenetapopt or a bispecific antibody. After the two agents were administered in combination, we observed encouraging efficacy, which prompted us to investigate this therapeutic approach systematically.
From a mechanistic perspective, bispecific antibody monotherapy has demonstrated substantial antitumor activity in RRMM, but some patients still develop primary or acquired resistance. Eprenetapopt targets the death receptors DR4 and DR5 on the surface of myeloma cells and acts as a death receptor agonist. Bispecific antibodies, meanwhile, target antigens such as BCMA or GPRC5D on the surface of myeloma cells.
Both agents act on targets associated with the tumor cell membrane. This combination strategy has a mechanistic rationale similar to dual-antigen targeting approaches that simultaneously target BCMA and GPRC5D. Previous studies have shown that targeting both BCMA and GPRC5D can improve efficacy in patients with RRMM, including those with extramedullary disease. Based on these findings, we hypothesized that eprenetapopt-mediated death receptor activation could enhance the activity of bispecific antibodies against cell-surface antigens, resulting in synergistic therapeutic effects.
The mechanistic advantage of this combination lies in the complementary roles of the two agents. As a DR4/DR5 agonist, eprenetapopt activates death receptor signaling to induce tumor cell apoptosis. Bispecific antibodies, by targeting BCMA or GPRC5D, facilitate T-cell-mediated immune killing of myeloma cells. Combining these approaches through two distinct membrane-associated targets could theoretically produce complementary mechanisms of action and synergistic efficacy.
This combination showed preliminary promise in a patient with severe blastoid plasmacytoma. Following this observation, we initiated the phase II clinical study to systematically evaluate its efficacy and safety.
Oncology Frontier – Hematology Frontier: Based on the data available to date, what efficacy and safety profile has eprenetapopt combined with bispecific antibodies demonstrated in RRMM? What findings are particularly noteworthy regarding deep responses, response durability, and adverse event management? Which patient populations may benefit most from this approach?
Professor Aijun Liu: The phase II study has enrolled 25 patients with RRMM as of the congress abstract submission deadline. The regimen appears to act rapidly: the overall response rate (ORR) exceeded 70% after just one treatment cycle. After two cycles, some patients with particularly difficult-to-treat disease had achieved complete remission, with the CR rate exceeding 45%.
These efficacy findings suggest that combining eprenetapopt, which acts through death receptors, with bispecific antibodies targeting cell-surface antigens may have substantial antitumor activity in RRMM, particularly in terms of achieving deep responses.
Regarding safety, the adverse events observed were mainly associated with bispecific antibody therapy and included hypogammaglobulinemia, infections, and cytokine release syndrome (CRS). Cytopenias were also primarily attributable to the bispecific antibodies. Eprenetapopt was well tolerated when administered on a weekly schedule, with essentially no significant hematologic toxicity, no hepatic or renal impairment, and no substantial increase in infection-related events.
Consequently, the incidence of adverse events with this combination was considerably lower than that reported with bispecific antibody monotherapy or combinations of two bispecific antibodies. In addition, hypogammaglobulinemia and CRS appeared to lessen with longer exposure to bispecific antibody treatment, suggesting that this combination may offer certain advantages in adverse event management.
In terms of patient populations, those with disease that has relapsed after multiple lines of treatment and those with triple-class-refractory disease, including resistance to anti-CD38 monoclonal antibodies, appear to derive substantial benefit. Patients with high-risk cytogenetic or genetic features may also benefit. However, achieving satisfactory outcomes remains challenging in patients with TP53 deletion or mutations, particularly when multiple high-risk genetic abnormalities coexist. These patients continue to represent a major therapeutic challenge.
Patients with extramedullary disease may also derive meaningful benefit from this combination.
Oncology Frontier – Hematology Frontier: Looking ahead, what role might this combination strategy play in multiple myeloma treatment? Could it move into earlier lines of therapy? What are the plans for subsequent research, and what opportunities remain for optimizing combination regimens and selecting patients?
Professor Aijun Liu: The regimen has shown encouraging efficacy and a favorable safety profile. Bispecific antibodies have now received approval for use in the second-line setting, following first relapse. The key potential value of this combination is that it may reduce the adverse events associated with bispecific antibody monotherapy while helping overcome limitations related to resistance to bispecific antibodies.
When efficacy, safety, and cost are considered together, this combination may offer advantages over bispecific antibody monotherapy. For patients who require bispecific antibody treatment, this approach could help optimize outcomes across all three dimensions.
Regarding the movement of immunotherapy into earlier treatment lines, future research should further explore combinations of effective therapeutic agents. For example, the efficacy of BCMA-targeted CAR T-cell therapy has been well established. Combining it with bispecific antibodies or other relatively effective and cost-efficient agents could substantially improve outcomes in RRMM.
Beyond BCMA, GPRC5D, and FcRH5 antigens on the surface of myeloma cells, combining these approaches with death receptor agonists may further enhance therapeutic efficacy. In addition, drugs targeting three distinct targets in myeloma may become available in the near future.
From a broader perspective, the significance of this study extends beyond the introduction of a new combination strategy. It offers a new approach to treating RRMM: targeting different functional pathways associated with the tumor cell membrane to achieve complementary mechanisms and synergistic efficacy, while optimizing dosing schedules to reduce adverse events.
As further combination strategies are explored and more prospective clinical data accumulate, the treatment landscape for RRMM is expected to continue improving.
Expert Profile
Professor Aijun Liu
Beijing Chao-Yang Hospital, Capital Medical University
Deputy Director, Department of Hematology; Chief Physician; Professor; Master’s Supervisor.
- Vice Chair and Secretary-General, Hemostasis and Thrombosis Branch, China Association for Medical Education
- Standing Committee Member, Myeloma Branch, China Association for Medical Education
- Standing Committee Member, Pharmacy Committee, Chinese Women’s Physicians Association
- Committee Member, Hematology Committee, Chinese Women’s Physicians Association; Standing Committee Member, Myeloma Group
- Vice Chair, Hematology Committee, Beijing Association of Integrative Medicine
- Vice Chair, Hematology Committee, Beijing Perioperative Medicine Research Association
- Standing Committee Member, Hematology Committee, Beijing Association of Integrated Medicine
- Standing Committee Member, Hemostasis and Thrombosis Branch, Beijing Cancer Prevention and Treatment Association
- Standing Committee Member, Precision Diagnosis and Treatment Committee for Hematologic Malignancies, Beijing Health Promotion Association
- Visiting Scholar, VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, USA (2015–2016)
Research interests: Hematologic malignancies, particularly plasma cell neoplasms, and the relationship between cancer and coagulation.
Professor Liu has published more than 50 SCI-indexed and core-journal papers as first or corresponding author in journals including Journal of Hematology & Oncology (JHO) and Blood Research (BR). She has also served as deputy editor or contributing author for eight monographs and textbooks. She received the First Prize of the Science and Technology Innovation Award from the China Association for Medical Education as the second contributor.
