From January 5th to 7th, 2024, the Fourth China Hematology Development Conference (CASH) was grandly held in Tianjin. Continuing the theme of "Big Hematology, Big Health, Big Healthcare," the conference focused on the core development directions of hematology and the major disciplinary issues faced in basic research, translation, and clinical diagnosis and treatment in the new era. At the conference, Professor LuGui Qiu , the director of the Lymphoma Diagnosis and Treatment Center at the Hematology Hospital of the Chinese Academy of Medical Sciences (Institute of Hematology, CAMS), delivered an insightful report on "The Road to Cure Multiple Myeloma: Dilemmas, Challenges, and Prospects." The "Oncology Frontier - Hematology Frontier" invited Professor Qiu to interpret this topic and deeply analyze the significant advancements in the treatment of multiple myeloma, sharing his profound ideas.
“Oncology Frontier – Hematology Frontier“: What are the challenges and obstacles on the path to curing multiple myeloma?
Professor LuGui Qiu : Multiple myeloma (MM), as one of the common malignant hematological tumors in the middle-aged and elderly population, remains incurable for the vast majority of patients. The main challenge in curing MM lies in the fact that, despite the widespread use of main treatments like proteasome inhibitors, immunomodulators, CD38 monoclonal antibodies, and autologous stem cell transplantation (ASCT) over the past two decades, which have extended the median overall survival (mOS) of patients from 2-3 years to over 10 years, most patients still cannot be cured. Multiple relapses and refractory cases are unavoidable in many patients, imposing a heavy burden on patients, families, and society as a whole. In terms of treatment challenges, I believe there are several aspects: (1) MM is highly heterogeneous. Some patients with a good prognosis can have a progression-free survival (PFS) of over 5 years and an overall survival (OS) of over 10 years after standard treatment, but a small portion of patients have a median OS of less than 3 years under standard treatment (e.g., VRd±ASCT), and even some high-risk MM patients have a median OS of less than 2 years. This necessitates early identification of high-risk and ultra-high-risk MM patients at diagnosis or early relapse, to provide personalized treatment plans. (2) The efficacy and survival outcomes for high-risk and ultra-high-risk MM patients under standard treatment are poor, and exploring more effective treatment plans is one of the current challenges. (3) As the number of MM treatment drugs increases, it is a significant challenge to develop rational treatment plans for first-line and multiple-line relapse treatments based on differences in patients’ clinical and biological characteristics, physical condition, age, and socio-economic factors, to layout the best overall treatment model for patients.
“Oncology Frontier – Hematology Frontier“: Can you discuss the value of minimal residual disease (MRD) monitoring in MM treatment and the MM treatment strategies based on MRD levels?
Professor LuGui Qiu : In MM treatment, achieving undetectable minimal residual disease (uMRD) is one of the preliminary goals, especially for high-risk MM patients, as achieving deep remission is crucial for converting to longer PFS and OS. However, it is important to have a dialectical view of the value of MRD monitoring in MM, as it cannot be equated with its value in acute leukemia. This is because: (1) The heterogeneity of MM is much greater than that of acute leukemia; (2) The sensitivity of MRD detection in MM patients is still not high enough, and the distribution of MM tumor cells in the bone marrow is uneven, which can lead to significant sampling bias and false-negative MRD results; (3) Not all MM patients need to achieve uMRD to realize long-term survival. For example, a recent study by our team found that about 5% of MM patients, despite not achieving deep remission and uMRD, had very slow disease progression and still achieved good long-term survival, with a median PFS of over 5 years and a median OS of over 10 years. We refer to these patients as MGUS-like. For such patients, pursuing uMRD status is unnecessary, especially in elderly patients, where treatment should balance between depth of remission, quality of life, treatment benefit, and side effects.
Treatment strategies driven by minimal residual disease (MRD) levels have already become routine and mature in the treatment of childhood acute lymphoblastic leukemia (ALL) and adult acute leukemia, including acute myeloid leukemia (AML) and ALL. Currently, in the field of multiple myeloma (MM), MRD-driven treatment is also being explored. However, this approach is not suitable for all MM patients. I believe it is more applicable to younger patients who can tolerate high-intensity treatment and are suitable for autologous stem cell transplantation (ASCT). For example, in the MASTER study, an MRD-driven treatment strategy was applied. For high-risk MM patients, after diagnosis, 4 cycles of D-KRd (daratumumab, carfilzomib, lenalidomide, and dexamethasone) induction therapy were administered, followed by MRD testing. Then, ASCT and MRD testing were conducted. If MRD was negative twice consecutively, treatment could be stopped. Conversely, if any test was positive, 4 more cycles of D-KRd consolidation treatment plus MRD testing were conducted. Treatment would be stopped if MRD turned negative; if still positive, the patient would enter the maintenance therapy phase. The results of this study showed that MRD-driven treatment achieved impressive efficacy, to some extent overcoming the poor prognosis brought by high-risk factors, achieving a 4-year PFS of 55% for double-hit and triple-hit MM patients.Overall, MRD-driven treatment is not suitable for all MM patients, and further research is needed to clarify its value.
“Oncology Frontier – Hematology Frontier“: The combination of Daratumumab with VRD (bortezomib, lenalidomide, and dexamethasone) and subsequent ASCT intensification has made progress in first-line treatment for transplant-eligible MM patients. Could you talk about the value of this regimen in achieving a cure for MM?
Professor LuGui Qiu : After several large-scale, head-to-head clinical trials, VRD±ASCT has established its position in the standard first-line treatment of MM. Based on the results of studies like SWOG S0777, IFM2009, and DETERMINATION, two points have been confirmed: (1) VRD or VRD-lite can be the standard first-line treatment for MM; (2) In the current treatment paradigm, ASCT still holds a very firm position in MM treatment. After the introduction of Daratumumab, whether a four-drug regimen (Daratumumab plus three drugs) is superior to a three-drug regimen, and even if a four-drug regimen can replace ASCT, are topics currently being explored. At the 2023 ASH conference, an LBA-1 abstract from the PERSEUS study was presented. This study, a phase III clinical trial built on the GRIFFIN phase 2 study, compared the efficacy of VRD± Daratumumab +sequential ASCT in transplant-eligible MM patients. After a median follow-up of 4 years, results showed that the addition of Daratumumab significantly improved 4-year PFS (from 67.7% to 84.3%, HR=0.42; 95%CI: 0.30-0.59; P<0.0001), indicating that a four-drug combination is superior to a three-drug regimen for patients who can tolerate high-intensity treatment. In fact, a study conducted by European researchers had previously confirmed this conclusion.
The advent of new drugs like Daratumumab can further improve the deep response rate (including uMRD) in newly diagnosed and relapsed/refractory MM patients, and can be translated into longer PFS. However, whether it can ultimately improve OS still needs further research. Overall, these studies prove that adding new drugs in combination can bring certain therapeutic benefits, and undergoing ASCT still has significant value, maintaining its important and firm position.
Regarding the cure of MM, we hope to achieve longer survival and even cure in high-risk MM patients by applying CAR-T or bispecific antibodies immunotherapy under the guidance of prognosis stratification, based on the existing treatment modalities. Therefore, we propose a strategy for curing MM, namely a dynamically prognosis-stratified driven overall treatment strategy for MM, and a series of clinical studies are currently being conducted in hopes of finding a path to cure MM.
