Although multiple myeloma (MM) is mostly seen in the elderly, it is not uncommon in young adults under 50-55 years of age. In recent years, with the application of autologous hematopoietic stem cell transplantation and new drugs such as bortezomib, thalidomide, and ralidomide in MM, the response rate and prognosis of MM have been significantly improved, but it still cannot cure MM. allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is becoming more and more accepted as an effective means of treating MM. Wenrong Huang, Department of Hematology, Beijing 301 Hospital
Advantages of allogeneic hematopoietic stem cell transplantation (Allo-HSCT): Although Allo-HSCT has been used for MM treatment since 1980, there are still controversies. On the one hand, Allo-HSCT can remove tumor cells by high-dose chemotherapy, on the other hand, there are no contaminated tumor cells in the graft, and it also has the immune effect of graft-versus-myeloma (GVM), which is the only means to cure MM at present. effect. Patriarca F et al. in Italy recently reported a significant advantage of Allo-HSCT in relapse-refractory patients, with a 2-year PFS of 42% in 75 patients with HLA-compatibility and only 18% in 94 patients without HLA-compatibility. Recent French findings suggest that Allo-HSCT may also significantly improve patient outcomes and survival prognosis in patients with primary MM with high-risk factors. The European Myeloma Collaborative Group compared autologous hematopoietic stem cell transplantation (AHSCT) with Allo-HSCT in 357 primary MM patients from 2001-2005, with a median follow-up of 61 months, and confirmed that Allo-HSCT was superior to AHSCT in terms of 5-year complete remission and survival rates, and that the 5-year disease recurrence rate was significantly lower with Allo-HSCT than with AHSCT (43%). Allo-HSCT was significantly lower than AHSCT (43% vs. 78%). Therefore, the long-term efficacy of Allo-HSCT for MM was better than conventional treatment or AHSCT for both primary and relapsed refractory patients.
Problems with Allo-HSCT for MM: The main reason limiting the use of Allo-HSCT in MM is that previous data reported transplant-related mortality (TRM) in MM after Allo-HSCT as high as 30-50%. Analysis of data from these early studies of high TRM in Europe and the United States in the 1980s and 1990s revealed that the main causes of high TRM were: poor general condition of patients, mega-dose pretreatment regimens, severe GVHD and opportunistic infections. Because most MM patients are older, few patients with previous Allo-HSCT are primary patients, almost all are relapsed refractory patients, have received multiple chemotherapy regimens, and patients have greater impairment of organ function and fitness; pretreatment regimens used for MM allografts are significantly more intense than the current standard Bu/Cy or TBI/Cy pretreatment regimens, with high pretreatment toxicities and the highest proportion of patients dying from multiple organ function The proportion of patients who die from multiorgan insufficiency is the highest; GVHD prophylaxis is mostly cyclosporine combined with short course of methotrexate, and the incidence of severe aGVHD is high; and the poor immune function of MM patients themselves, combined with poor general condition, heavy tissue damage of pretreatment regimen and severe GVHD make patients easy to complicate lethal infections.
How to reduce TRM associated with Allo-HSCT: Infectious complications of MM undergoing Allo-HSCT have been significantly controlled due to current improvements in supportive therapies and advances in antibacterial and antifungal drugs. Just as patients with chronic granulocytic leukemia cannot wait for an acute change of disease before performing Allo-HSCT, MM, as a disease that progresses relatively slowly but cannot be cured by conventional treatment, should also place Allo-HSCT in the overall treatment strategy once diagnosed in patients with primary MM, especially those with high-risk factors or young primary patients, and should not wait until the relapsed refractory state where they are not sensitive to various The application of reduced-dose pretreatment (RIC) regimens for Allo-HSCT rather than mega-dose clearing pretreatment regimens can serve to reduce tumor load while maintaining the GVM effect and significantly reducing TRM. The European Myeloma Collaborative Group recently reported that primary MM patients receiving Allo-HSCT with RIC had a 2-year TRM of only 12%. A recent analysis by the International Bone Marrow Transplant Registry (CIBMTR) of data related to Allo-HSCT for MM from 1989-2005 also showed a significant decrease in TRM in recent years, with a significant reduction in 100-day TRM from 33% between 1989-1994 to 17% from 2001-2005, and a reduction in 5-year TRM from 40% to 28%. The RIC regimens reported in the last decade or so include two major categories in terms of intensity: reduced-dose clearing regimens and non-clearing regimens, with reduced-dose clearing regimens mostly based on fludarabine combined with marfalan, and non-clearing regimens mostly based on low-dose systemic radiotherapy ± fludarabine. The incidence of 3rd-4th degree aGVHD, extensive cGVHD and transplantation-related mortality did not differ significantly between the two types of RIC regimens, but reduced-dose clear myeloablative pretreatment had better donor cell implantation rates, higher treatment response rates and lower incidence of disease progression than non-clear myeloablative pretreatment, so the intensity of transplantation pretreatment should not be reduced in order to reduce TRM. As a proteasome inhibitor, bortezomib has not only superior anti-myeloma effects, but also immunosuppressive effects. Some animal model studies have reported that bortezomib significantly reduces the incidence and severity of aGVHD after Allo-HSCT, and clinical studies have reported that bortezomib is effective in treating cGVHD. Therefore, bortezomib combined with myeloablative RIC pretreatment can further reduce the tumor load in vivo and enhance the post-transplant GVM effect; meanwhile, the immunosuppressive effect of bortezomib can be used to prevent aGVHD and reduce the incidence of severe aGVHD after transplantation to reduce TRM. The incidence was reduced from about 30% to 10%.
How to improve the efficacy of Allo-HSCT for MM: Reducing pre-Allo-HSCT tumor load, TRM and post-transplant disease recurrence are the 3 most important aspects to improve the efficacy of MM. Measures to reduce TRM are as described previously, and reduction of pre-Allo-HSCT tumor load is mainly performed by adjusting pre-transplant therapies, including AHSCT before Allo-HSCT, application of chemotherapy regimens containing immunomodulators such as thalidomide and new agents such as bortezomib as a proteasome inhibitor. Given that the aim of AHSCT before Allo-HSCT was to minimize the tumor load and to improve the efficacy of Allo-HSCT by preferably achieving VGPR or above before Allo-HSCT. Compared with previous chemotherapy, which could only achieve VGPR or above in 5-10% of patients, the current bortezomib combined with ralidomide and dexamethasone regimen could achieve VGPR or above in nearly 70% of MM patients, which could reduce the tumor load to a very low level. In fact, post-transplant disease recurrence is the real problem of allo-HSCT for MM. post-Allo-HSCT maintenance therapy and donor lymphocyte infusion may be an effective means to prevent disease progression or recurrence. The maintenance therapy and donor lymphocyte infusion after Allo-HSCT may be an effective tool to prevent disease progression or relapse. Bortezomib and thalidomide may be the most relevant in maintenance therapy, as both drugs have good anti-myeloma effects on the one hand, and both drugs have a therapeutic effect on cGVHD on the other, perhaps preventing the development of extensive chronic GVHD. Donor lymphocyte infusion is an effective anti-myeloma relapse measure, but donor lymphocyte infusion may trigger severe GVHD and bone marrow hematopoietic void in patients, and should be applied with caution. Given the inert progression of myeloma cell biology, donor lymphocyte infusion is best started at small doses, using a stepwise escalation of lymphocyte infusion doses. With advances in transplantation techniques and improved supportive therapy, the transplant-related mortality of MM after Allo-HSCT has decreased significantly compared to the past. Therefore, allogeneic hematopoietic stem cell transplantation should be performed as early as possible after minimizing the tumor load in patients younger than 55-60 years of age, with HLA-compatible donors, relapsed refractory or primary MM patients with poor prognostic factors at diagnosis, if there is no contraindication to transplantation. Stem cell transplantation.