Editor’s Note: Induction therapies with high remission rates, combined with high-dose chemotherapy and autologous stem cell transplantation (ASCT), have significantly improved the prognosis for multiple myeloma (MM) patients. Despite this, patients still inevitably experience disease progression or relapse. One of the key goals in this research field is how to maintain remission in patients after induction therapy and ASCT. The 50th European Society for Blood and Marrow Transplantation (EBMT) annual meeting took place in Glasgow, UK, from April 14 to 17, 2024. The conference focused on the latest advancements in stem cell transplantation and cellular therapy, driving better clinical outcomes for patients with hematological diseases and cancers. At this conference, Professor Jean-Luc Harousseau, Chairman of the French National Health Authority and Director of the René Gauducheau Cancer Center at the University of Nantes, delivered an insightful presentation on optimizing induction therapy strategies for multiple myeloma patients before ASCT. “Hematology Frontier” invited Professor Harousseau to share his insights on continuously optimizing pre-ASCT induction therapy for multiple myeloma patients.
“Hematology Frontier – Hematology Frontier”: Could you please explain the entire ASCT process? What is the main purpose of pre-ASCT pretreatment, and how crucial is this step for the success of ASCT?
Professor Harousseau: Currently, ASCT remains the standard treatment for younger patients without comorbidities. Numerous randomized trials have shown that prioritizing ASCT, unless new treatments are introduced, significantly benefits patients in terms of efficacy, not only by increasing the objective response rate (ORR) but also by increasing the proportion of patients achieving minimal residual disease (MRD) negativity. This leads to longer progression-free survival (PFS). This is why, despite the risks associated with this strategy, it remains preferred, particularly in European countries.
Discussing the entire ASCT regimen, it begins with induction therapy before ASCT, aimed at significantly reducing or minimizing tumor burden. Following this, the patient undergoes ASCT after achieving complete remission (CR), continues with the same regimen as the induction to consolidate the results and further improve outcomes, and finally undergoes maintenance therapy, which can last up to three years. The choice of induction therapy significantly impacts the effectiveness of ASCT. Currently, the classical regimen is a triplet therapy—either bortezomib or carfilzomib, plus lenalidomide or thalidomide, and dexamethasone (such as VRd, VTd, or KRd), usually for 4-6 cycles.
Recent studies have shown that the inclusion of anti-CD38 monoclonal antibodies and the application of a quadruplet regimen can achieve deeper tumor remission and significantly improve survival for multiple myeloma patients. In randomized trials, adding daratumumab or isatuximab as part of a quadruplet regimen for both induction and consolidation further enhances treatment efficacy, particularly in terms of CR rates, stringent complete response rates (sCR), and MRD negativity.
“Hematology Frontier – Hematology Frontier”: In terms of choosing a pretreatment regimen, what strategies were commonly used in the past to maximize the elimination of cancer cells and reduce disease burden?
Professor Harousseau: Pretreatment is one of the critical factors affecting the success or failure of transplantation. “Pretreatment” refers to the use of radiation, chemotherapy, and immunosuppressive treatments before transplantation to facilitate the successful implantation of the graft and maximize the elimination of abnormal or cancer cells. The primary goal of pretreatment is to eradicate abnormal or cancer cells in the patient’s body to minimize the risk of relapse. In the past, attempts were made to purify the bone marrow with chemotherapy, even using antibodies in the graft, but this proved too complex and toxic. Therefore, we decided to use peripheral blood stem cells to reduce the proportion of malignant cells in the graft. However, malignant cells may still be present in the graft even when using peripheral blood stem cells. The advantage of high-dose therapy is that when we destroy the patient’s bone marrow, the cells that repopulate the marrow are mostly healthy cells. Therefore, minimizing tumor burden before transplantation is always crucial, which is the goal of induction therapy.
“Hematology Frontier – Hematology Frontier”: Currently, efforts to improve ASCT efficacy mainly focus on optimizing induction therapy to increase the complete remission rate. Could you tell us about the main advancements in this area?
Professor Harousseau: As previously mentioned, this is a gradually improving process. In multiple myeloma patients, we started with the VAD chemotherapy regimen (vincristine, doxorubicin, and dexamethasone) and then gradually introduced thalidomide and bortezomib since 2000 with doublets—thalidomide-dexamethasone or bortezomib-dexamethasone. We then moved to triplet regimens after 2005 (VRd, VTd, or KRd). Finally, we now have quadruplets with anti-CD38 antibodies. Ultimately, our goal is to increase the CR rate and the proportion of patients achieving MRD negativity post-transplant. It is worth mentioning that after induction therapy, autologous transplantation, and consolidation treatment, we also have maintenance therapy. Post-transplant maintenance is a very important part of the treatment journey for multiple myeloma patients, commonly involving lenalidomide or more recently, lenalidomide combined with anti-CD38 antibodies, aimed at prolonging the duration of remission and, in some cases, deepening the level of response. Therefore, the current strategy for treating younger multiple myeloma patients includes induction therapy, autologous transplantation, and consolidation, followed by long-term maintenance, with the hope of achieving long-term progression-free survival for the patients.
