Editor's Note: Extramedullary disease (EMD), an aggressive manifestation of multiple myeloma, presents longstanding challenges in clinical management, including substantial biological heterogeneity, difficulties in diagnosis and response assessment, resistance to conventional therapies, and a lack of high-level evidence from clinical trials. During the 2026 Cross-Strait Hematology Conference, Prof. Cai Zhen of the First Affiliated Hospital of Zhejiang University School of Medicine spoke with Oncology Frontier – Hematology Frontier about the key challenges of EMD, including target antigen escape, an immunosuppressive microenvironment, and difficulties in imaging-based response assessment. He also reviewed the latest advances and evolving treatment strategies involving bispecific antibodies, CAR-T-cell therapy, and novel antibody-drug conjugates (ADCs), providing authoritative and cutting-edge clinical insights into improving outcomes for patients with this high-risk disease subtype.Oncology Frontier – Hematology Frontier: Extramedullary disease is a high-risk marker of poor prognosis in multiple myeloma, but there remains considerable clinical debate regarding its definition, the optimal timing of imaging screening, and early identification. Based on current clinical practice, could you discuss the major challenges and unmet needs in the precision diagnosis and management of EMD?
Prof. Cai Zhen: Extramedullary disease (EMD) is a highly aggressive manifestation of multiple myeloma (MM) and is extremely challenging to treat. Currently, the major challenges in EMD management can be broadly categorized into four areas: biological characteristics, diagnostic assessment, therapeutic approaches, and clinical research.
First, EMD is highly heterogeneous at the biological level. The extramedullary lesions and intramedullary tumor clones within the same patient are often not completely identical. Extramedullary clones are more likely to harbor high-risk cytogenetic abnormalities such as del(17p) and 1q21 amplification, and MAPK pathway mutations are also more frequent. In addition, extramedullary lesions often exhibit downregulation or loss of therapeutic targets such as CD38, BCMA, and GPRC5D, resulting in target-mediated treatment escape. At the same time, extramedullary masses can develop hypoxic and highly immunosuppressive microenvironments. Even when immune therapies such as CAR-T cells or bispecific antibodies are able to infiltrate these lesions, the immune cells can rapidly become exhausted, making it difficult to sustain an effective antitumor response. Some lesions may also develop fibrous capsules that create a physical barrier, further limiting the penetration of drugs and immune cells.
Second, there are significant challenges in diagnosis and response assessment. The definition of EMD remains controversial. Paraskeletal extramedullary lesions and true hematogenous extramedullary disease have significantly different prognoses, yet they can easily be confused in clinical practice. PET/CT is an important tool for detecting EMD, but it has not yet been universally adopted, and the detection of some deep-seated lesions, such as those involving the central nervous system, is often substantially delayed. In terms of response assessment, the International Myeloma Working Group (IMWG) criteria primarily focus on bone marrow involvement and M-protein, while soft-tissue masses generally require reference to solid-tumor response criteria. Even when the bone marrow achieves minimal residual disease (MRD) negativity, extramedullary tumors may persist. Relying solely on hematologic indicators can therefore underestimate residual disease and lead to an inaccurate assessment of treatment response, which is unfavorable for early identification of the risk of disease progression.
Third, current treatment approaches have significant limitations, and there is no standardized treatment strategy. Conventional agents and combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, have significantly lower objective response rates in EMD than in conventional intramedullary myeloma. Although novel immunotherapies such as CAR-T cells and bispecific antibodies can achieve relatively high response rates in patients with EMD, the duration of response is considerably shorter. Combined with factors such as target loss and local immunosuppression within the lesions, the risk of early relapse remains extremely high. In addition, EMD treatment may require local interventions such as radiotherapy or surgery, but there is still no consensus regarding how and when to combine local and systemic therapies. In particular, for EMD involving special sites such as the central nervous system, the challenge of achieving adequate drug penetration across physiological barriers remains unresolved.
Finally, at the clinical trial level, the majority of studies exclude patients with EMD, resulting in a lack of high-level evidence-based data in this field. There are currently limited treatment recommendations specifically stratified for EMD, and individualized treatment relies largely on retrospective data and clinical experience. This has significantly constrained further improvements in the overall standard of EMD management.
Oncology Frontier – Hematology Frontier: Compared with intramedullary lesions, extramedullary myeloma is often resistant to first-line agents such as proteasome inhibitors and immunomodulatory drugs, making treatment particularly challenging. Could you discuss the overall treatment strategies for newly diagnosed and relapsed/refractory patients with EMD? How have next-generation therapies such as bispecific antibodies, CAR-T cells, and ADCs performed against extramedullary lesions?
Prof. Cai Zhen: In recent years, the rapid development of T-cell–redirecting immunotherapies has brought important breakthroughs to the treatment landscape of extramedullary myeloma. These advances have mainly involved bispecific antibodies, CAR-T-cell therapy, and novel small-molecule agents/antibody-drug conjugates (ADCs), while the overall treatment philosophy has also undergone significant changes.
First, bispecific antibodies, particularly dual-target combinations, have provided a new later-line treatment option for patients with EMD. Single-target BCMA bispecific antibodies have demonstrated weaker efficacy against extramedullary lesions than in patients without EMD. However, a phase II clinical study evaluating a combination of BCMA- and GPRC5D-targeted bispecific antibodies reported an overall response rate (ORR) of 79% specifically among patients with EMD, with more than half of patients achieving complete response (CR) or deeper responses and a 12-month progression-free survival (PFS) rate of 61%. This provides patients with EMD who have failed multiple lines of therapy with an “off-the-shelf” treatment option that does not require individualized cell manufacturing. Objectively, however, compared with patients without EMD, the depth and durability of responses remain inferior in the EMD population. Antigen escape and local immunosuppression remain major challenges that need to be addressed.
Second, CAR-T-cell therapy remains a key approach for achieving deep responses in EMD. Conventional BCMA CAR-T therapy can achieve relatively high objective response rates in patients with EMD. However, because of factors such as antigen loss, the duration of response is generally shorter than that observed in patients with conventional bone marrow myeloma, and relapse rates remain high. In recent years, dual-target CAR-T cells targeting BCMA and GPRC5D have emerged as an important therapeutic direction. Studies involving EMD cohorts have shown a very high rate of mass regression with this strategy, suggesting that it may partially overcome the antigen escape associated with single-target therapy and provide therapeutic benefit in patients with extramedullary relapse after failure of BCMA-targeted therapy. In addition, real-world data from China suggest that using CAR-T therapy at an earlier stage, before severe T-cell exhaustion develops, may be more conducive to controlling EMD. For EMD involving special sites such as the central nervous system, increasing clinical experience with cellular immunotherapy has also been accumulated, although sustained benefit remains relatively limited overall.
Finally, the emergence of novel small-molecule agents and ADCs has further expanded the treatment landscape. For example, novel agents such as selinexor, when combined with conventional triplet or quadruplet regimens, have demonstrated favorable lesion clearance in patients with newly diagnosed MM and EMD and may help some patients bridge to autologous hematopoietic stem cell transplantation. Meanwhile, GPRC5D-targeted ADCs have entered early-phase clinical studies and may provide additional treatment options for patients with EMD in the future.
Expert Profile
Prof. Cai Zhen
The First Affiliated Hospital of Zhejiang University School of Medicine
- MD, Zhejiang University Qiu Shi Distinguished Physician
- Second-level Professor, Chief Physician, Doctoral Supervisor
- Director, Multiple Myeloma Treatment Center
- Zhejiang Provincial High-Level Innovative Health Talent
- Chair, Hematology and Lymphoma Committee, Zhejiang Anti-Cancer Association
- Chair-elect, Hematology Branch, Zhejiang Medical Association
- Member, Hematology Branch, Chinese Medical Association
- Deputy Leader, Plasma Cell Disease Group, Hematology Branch, Chinese Medical Association
- Standing Committee Member, Hematologic Oncology Committee, Chinese Anti-Cancer Association
- Deputy Leader, Multiple Myeloma Group, Chinese Anti-Cancer Association
- Standing Committee Member, Hematology Immunology Committee, Chinese Society for Immunology
- Deputy Leader, CSCO China Autologous Hematopoietic Stem Cell Transplantation Working Group
