Editor's Note: At the European Hematology Association (EHA) 2025 Annual Congress, the special session on Multiple Myeloma (MM) was filled to capacity. The core focus of the meeting was the latest version of the clinical practice guidelines jointly released by the European Hematology Association and the European Myeloma Network (EHA-EMN). These guidelines, developed over several years through the dedicated collaboration of a team of top European experts, including Professor Meletios A. (Thanos) Dimopoulos and Professor Evangelos Terpos, systematically evaluated a vast body of literature, with the final results being officially published just before the congress in the internationally authoritative journal Nature Reviews Clinical Oncology. This article, based on the on-site presentation by EHA board member Professor Evangelos Terpos, provides an in-depth interpretation of these landmark guidelines, aiming to offer a cutting-edge reference for clinical and research colleagues worldwide.Guideline Update Background: Addressing the Unprecedented Complexity of Treatment Choices
At the beginning of the meeting, Professor Peter Sonneveld, President of EHA-EMN, delivered the opening remarks. He pointed out that four years have passed since the last version of the guidelines was published, and compared to eight years ago, the field of multiple myeloma treatment has undergone transformative changes. Innovative drugs such as anti-CD38 monoclonal antibodies (e.g., daratumumab, isatuximab), bispecific antibodies, and Chimeric Antigen Receptor T-cell (CAR-T) therapies have steadily advanced from later lines of therapy to the frontline setting, significantly expanding the clinician’s therapeutic arsenal. Professor Sonneveld emphasized: “We now have far more drug options than ever before, making treatment decisions, from frontline to later lines, unprecedentedly complex. Therefore, an up-to-date, authoritative guideline that can direct daily practice is crucial for every clinician.” This new guideline was created to meet this challenge. It not only integrates the latest clinical evidence up to May 31, 2025, but also provides clear recommendations for areas where evidence is still emerging, based on multiple rounds of expert consensus.
Innovations in Diagnosis and Risk Stratification: Redefining High-Risk Myeloma
The new guidelines first introduce significant updates to the diagnostic criteria and risk assessment system for multiple myeloma. Professor Terpos highlighted the brand-new definition of high-risk disease, recently published in the Journal of Clinical Oncology. According to the new standard, traditional cytogenetic abnormalities such as t(4;14), t(14;16), and t(14;20), when present in isolation, are no longer considered high-risk features. They must co-occur with gain/amplification of 1q or monoallelic deletion of 1p to be classified as high-risk factors. Similarly, an isolated 1q gain/amplification is no longer a high-risk marker. Other factors included in the high-risk definition are: deletion of 17p detected in over 20% of sorted plasma cells, TP53 mutations, biallelic deletion of 1p32, and high levels of β-2 microglobulin in the context of normal creatinine. This refined risk stratification lays a solid foundation for the subsequent selection of personalized treatment strategies.
In diagnostic workup, the guidelines emphasize the central role of Minimal Residual Disease (MRD) testing. MRD assessment is required at diagnosis and after achieving a Complete Response (CR), with a recommendation for reassessment every 12 months after achieving MRD negativity to confirm sustained MRD-negative status. In terms of imaging, diffusion-weighted imaging MRI (DWI-MRI) has been added alongside PET-CT as a preferred method for diagnosis and confirmation of MRD negativity, as it can more clearly reveal lesions within the bone marrow.
The New Standard for First-Line Treatment: Quadruplet Regimens Lead the Change
First-line therapy is the centerpiece of this guideline update, with quadruplet combination regimens now established as the new standard for both transplant-eligible and transplant-ineligible patients.
For patients eligible for Autologous Stem Cell Transplantation (ASCT), the guidelines prioritize quadruplet induction regimens based on daratumumab or isatuximab combined with VRd (bortezomib, lenalidomide, dexamethasone). This recommendation is primarily based on the landmark PERSEUS study. The study’s results showed that compared to the VRd triplet regimen, the Dara-VRd quadruplet regimen increased the four-year Progression-Free Survival (PFS) rate from 67% to 84%. Even more excitingly, modeling data presented by Professor Sonneveld at the EMN meeting projected that the median PFS for the Dara-VRd regimen is as long as 17 years, compared to just 7.3 years for the VRd group, marking a historic leap in life expectancy for younger patients. Furthermore, the Dara-VRd regimen demonstrated overwhelming superiority in achieving sustained MRD negativity (two-year sustained MRD negativity rate of 56% vs. 23%).
For transplant-ineligible patients, based on the exceptional data from the IMROZ and CEPHEUS studies, Isa-VRd and Dara-VRd are also established as standard treatments. The IMROZ study confirmed that, compared to VRd, Isa-VRd could increase the five-year PFS rate from 45% to 63%. Data from the CEPHEUS study showed that the Dara-VRd regimen could deliver a projected median PFS of up to 100 months (over 8 years) for elderly patients. For frail, elderly patients with poor performance status, the classic MAIA regimen (Dara-Rd) remains a core option, and its dexamethasone-free modified version, Dara-R, has also shown superior survival benefits.
A Refined Treatment Pathway for Relapsed/Refractory Multiple Myeloma
For Relapsed/Refractory Multiple Myeloma (RRMM), the new guidelines provide a highly refined and individualized treatment pathway. The core decision-making point is whether the patient is refractory to lenalidomide and an anti-CD38 monoclonal antibody.
Professor Terpos detailed the preferred options for different scenarios. For patients refractory to lenalidomide but sensitive to anti-CD38 monoclonal antibodies, preferred options include the CAR-T therapy Cilta-cel, Belantamab-pom-dex (an antibody-drug conjugate combined with pomalidomide and dexamethasone), and Dara/Isa-Kd. For “dual-refractory” patients who are resistant to both lenalidomide and anti-CD38 monoclonal antibodies, the guidelines clearly state that Cilta-cel and Belantamab-pom-dex are the current first choices. This recommendation is strongly supported by studies such as DREAMM-7 and DREAMM-8, which show that Belantamab-based combinations can extend the median PFS to over 30 months compared to the standard of care.
The Rise of Cutting-Edge Immunotherapies: Application and Sequencing Challenges for CAR-T and Bispecifics
In the second-line and beyond setting, CAR-T therapies and bispecific antibodies have become mainstays of treatment. The guidelines include two CAR-T products (Idacel and Cilta-cel) and four bispecific antibodies (three targeting BCMA: Teclistamab, Elranatamab, Linvoseltamab; and one targeting GPRC5D: Talquetamab). Cilta-cel demonstrated astonishing efficacy in the CARTITUDE-4 study. For lenalidomide-refractory patients after 1-3 lines of therapy, its 30-month PFS rate reached an impressive 58%, far exceeding the 25% for standard of care. In the more heavily pretreated triple-class refractory patient population, the five-year Overall Survival (OS) rate with Cilta-cel is nearly one-third, with a median OS of 60.7 months, offering hope for long-term survival to this group of patients with an extremely poor prognosis.
Bispecific antibodies have also shown excellent performance, with Overall Response Rates (ORR) generally reaching 60%-70% in the triple-class refractory population. However, Professor Terpos also emphasized the unique side-effect management required for these drugs, especially the high risk of infection associated with BCMA-targeting bispecifics, which necessitates proactive prevention through measures like monthly infusions of immunoglobulin (IVIG).
A highly challenging clinical question is: how should these novel immunotherapies be sequenced? Professor Terpos cited data showing that if Cilta-cel is used after treatment with a BCMA-targeting bispecific antibody or an Antibody-Drug Conjugate (ADC), its efficacy is significantly diminished, with the median PFS plummeting to 5.3 months. Therefore, the current guideline recommendation is: “Available data suggest that for eligible patients, CAR-T cell therapy may need to be prioritized over BCMA-targeting ADCs or bispecific antibodies. Bispecific T-cell engagers may still be effective after CAR-T therapy, with Talquetamab possibly being the preferred option in this scenario.”
Expert Perspectives and Clinical Practice Outlook
During the Q&A session, the application of MRD in daily practice became a focal point. Professor Terpos responded that MRD testing is already deeply integrated into clinical practice and serves as a crucial basis for guiding treatment decisions. For example, in the PERSEUS study, patients who achieve sustained MRD negativity can discontinue daratumumab maintenance therapy. He further shared a study indicating that standard-risk patients who remain in sustained MRD negativity for three years have an extremely low relapse rate after stopping all maintenance therapy. This suggests the ultimate goal of a “treatment-free” future may be achievable, though this still requires confirmation from large-scale prospective studies.
In summary, the release of the new EHA-EMN 2025 guidelines represents a paradigm shift in the field of multiple myeloma treatment. It not only establishes the central role of quadruplet regimens in first-line treatment but also provides a clear pathway and sequencing principles for the clinical application of cutting-edge immunotherapies like CAR-T and bispecific antibodies. This guideline, a culmination of Europe’s top expertise, will profoundly influence clinical practice worldwide, leading the diagnosis and treatment of multiple myeloma into a new era of greater precision, efficacy, and promise.
