Editor's Note: The 2025 European Hematology Association (EHA) Annual Congress was grandly convened in Milan, Italy, bringing together the world's top hematology experts for an academic feast. At this congress, Professor Jesús San Miguel of the University of Navarra Clinic in Spain was honored with EHA Lifetime Achievement Award for his revolutionary contributions to the field of Multiple Myeloma (MM). In his award lecture and keynote report, titled "Curing Myeloma: A Long and Winding Road," Professor San Miguel systematically reviewed his 45-year research journey and strategically proposed five core pillars for achieving a cure for MM, charting a clear course for the future of the field.

As one of the most challenging malignancies in modern hematology, the treatment of multiple myeloma has made significant strides over the past two decades. However, achieving the ultimate goal of a “cure” remains a dream pursued relentlessly by researchers worldwide. At this year’s EHA Congress, a titan in the field, Professor Jesús San Miguel, used his life’s work as a blueprint to sketch a clear roadmap toward a cure.

Professor San Miguel began his report with humility: “I am sure that many of you in this room deserve this honor more than I do, but in any case, this provides a valuable opportunity for me to share our team’s dream—to cure myeloma.” His presentation was structured around five core pillars, profoundly revealing the essence of translational medicine from basic research to clinical practice.

Deep Dive into Pathological Mechanisms: Exploring the Four Key Targets to Cure Myeloma

To cure a disease, one must first deeply understand its pathogenesis. Professor San Miguel pointed out that his team’s research focuses on four key cellular compartments to identify the unique signatures of high-risk clones.

First is the clonal compartment. Research data shows that clonal B-lymphocyte proliferation may exist 20 to 30 years before an MM diagnosis, providing clues to the disease’s very early origins. Second is the immune system. The plasma cell expansion in MM is accompanied by immune dysfunction resulting from interactions among the host, the tumor, and the microenvironment. Therefore, immune monitoring has shown potential beyond Minimal Residual Disease (MRD) monitoring in improving diagnostic risk models, predicting survival, assessing infection risk, and even guiding the timing of immunotherapy.

The third key component is Circulating Tumor Cells (CTCs). Through single-cell transcriptomic analysis, Professor San Miguel’s team discovered a high overlap between CTCs and bone marrow plasma cells. Their dissemination does not stem from specific genetic events but may be a consequence of tumor cells being forced into the peripheral blood to seek new “soil” for growth under a hypoxic and proinflammatory microenvironment. Clinically, the number of CTCs has been proven to be a powerful prognostic indicator, capable of identifying occult plasma cell leukemia, and holds promise as a novel method for MRD detection. Lastly, MRD, as the “reservoir” for clonal evolution and disease relapse, is a target that must be eradicated to achieve a cure.

MRD-Guided Clinical Practice: From Prognostic Marker to the “Gold Standard” for New Drug Approval

On the road to a cure, accurately assessing the depth of treatment response is crucial. Professor San Miguel reviewed the evolution of MRD detection technologies, from initial explorations over two decades ago to today’s second-generation sequencing (NGS) and next-generation flow cytometry (NGF), which can detect one in a million cells.

“We have integrated data from over 12,000 patients, clearly demonstrating that patients who achieve MRD negativity have a significantly longer survival, regardless of whether they are in the transplant-eligible, transplant-ineligible, or relapsed setting,” Professor San Miguel emphasized. This landmark achievement directly led to the U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) voting unanimously (12:0) to accept MRD as an early endpoint for accelerated drug approval.

He cited an ongoing head-to-head clinical trial comparing autologous transplant with CAR-T cell therapy to illustrate the immense value of MRD as a surrogate endpoint. “If Progression-Free Survival (PFS) were the primary endpoint, this study might take 12-15 years to yield a conclusion. By analyzing MRD, however, we can obtain preliminary results in just a few years, which will greatly accelerate the speed at which innovative drugs reach patients.” Furthermore, monitoring MRD in peripheral blood using liquid flow cytometry or mass spectrometry is emerging as a new frontier to complement bone marrow assessments.

Moving Treatment Earlier: Early Intervention Lays the Foundation for Curing High-Risk Smoldering Myeloma

As with most solid tumors, early detection and intervention are prerequisites for curing MM. Professor San Miguel noted that High-Risk Smoldering Multiple Myeloma (SMM)—a precancerous state with over a 50% risk of progression to active MM within two years—is the ideal model for implementing this philosophy.

He shared the results of a landmark study published by the Spanish group over a decade ago: compared to observation, early intervention with lenalidomide and dexamethasone delayed disease progression by a full 7 years and reduced the risk of death by 43%. More recent studies have further confirmed that monotherapy with an anti-CD38 monoclonal antibody can also significantly reduce the risk of disease progression.

However, if the goal is a “cure,” more potent regimens are required. Professor San Miguel presented his team’s latest data: “In the transplant-eligible setting, we treated SMM patients with the same regimen used for active MM. At 70 months, as high as 94% of patients remained progression-free.” Currently, his team, in parallel with institutions like the Dana-Farber Cancer Institute, is actively exploring the potential of bispecific antibodies and CAR-T cell therapies in SMM patients, aiming to eradicate the disease at its earliest stage.

Revolutionizing Treatment Paradigms: From Quadruplet Combinations to Breakthroughs in Cutting-Edge Immunotherapies

In terms of treatment strategies, Professor San Miguel summarized the leaps made over the past 60 years. From the discovery of melphalan in 1960 to the approval of 19 new drugs or combinations in the last 20 years, survival rates for MM patients have improved dramatically. Currently, “quadruplet” combination therapies based on proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies have proven superior to traditional triplet regimens in multiple clinical trials, with the deep responses they induce even beginning to challenge the “cornerstone” status of autologous transplantation.

“For standard-risk patients, the median PFS predicted by these new regimens is an astonishing 10 to 17 years. This means a patient diagnosed at age 74 could potentially remain disease-free until the age of 84,” Professor San Miguel stated excitedly.

For high-risk patients with a poor prognosis, he proposed two cutting-edge strategies: first, “MRD-based early salvage intervention,” which involves promptly switching therapies upon detection of residual disease; and second, moving more potent immunotherapies (such as bispecific antibodies and CAR-T cells) to earlier lines of treatment and exploring “dual-target” attacks. Studies have shown that even in patients who are refractory after seven lines of therapy, CAR-T cell therapy can keep one-third of them disease-free after 5 years. Even more exciting, trispecific antibodies targeting two different antigens (such as BCMA and GPRC5D) have demonstrated remission rates approaching 100% in extremely heavily pretreated patients. Clinical trials using these revolutionary therapies in newly diagnosed patients are now fully underway.

Future Outlook: Marching Towards Personalized Therapy and the Realization of a Cure

“I have always envied my colleagues in the lymphoma field. I hope that in the future, we will not talk about ‘Multiple Myeloma,’ but ‘Myelomas’,” Professor San Miguel appealed at the end of his report. He believes that deeper insights from cell biology research, combined with the advent of innovative drugs, will ultimately lead us to achieve truly personalized precision medicine, thereby turning the dream of curing MM into a reality.

The entire presentation was not only a comprehensive showcase of scientific achievements but also a profound tribute to collaboration, mentorship, and the human spirit. As Professor San Miguel mentioned in his acceptance speech, his achievements would not have been possible without the support of his global colleagues, his Spanish team, friends, and family. He concluded by quoting Sartre: “Happiness is not in doing what you like, but in liking what you do.” As hematologists, being able to accompany patients through the joys and sorrows of their lives is, in itself, an unparalleled privilege and fortune.

Professor Jesús San Miguel enriched with over four decades of profound dedication and wisdom, has injected powerful confidence into the global hematology community. This “long and winding road” to a cure, as he depicted it, has become clearer and more hopeful than ever before, inspiring every professional in the field to continue the fight to ultimately defeat multiple myeloma.