Multiple myeloma (MM) is a common hematologic malignant disease, and how to individualize the treatment of MM patients has been a question for clinical hematologists to consider. Currently the National Comprehensive Cancer Network (NCCN) classifies MM patients into two categories, those who are suitable for hematopoietic stem cell transplantation and those who are not, based on the overall treatment strategy of MM patients. 2008 data from the International Bone Marrow Transplant Registry shows that MM is currently the malignant hematologic neoplasm with the highest number of completed transplant cases per year, nearly 90% of which are autologous hematopoietic stem/progenitor cell transplants ( Indications for MM transplantation are based on a combination of patient age, organ function and physical status. The treatment procedures for MM patients suitable for HSCT mainly include the selection of induction therapy, determination of transplantation timing, application of appropriate stem cell transplantation modality and post-transplantation maintenance therapy, and other major components. In this article, we only discuss the individualized treatment decisions suitable for patients with HSCT MM. Wenrong Huang, Department of Hematology, Beijing 301 Hospital
Selection of induction therapy regimen prior to transplantation
The efficacy of induction therapy directly affects the efficacy of subsequent autologous hematopoietic stem cell transplantation. the Bologna 96 clinical study confirmed that the CR/nCR rates for single and double AHSCT were 52% and 73%, respectively, for those who responded to induction therapy, whereas the CR/nCR rates for single and double AHSCT were only 11% and 12% for those who did not respond to induction therapy. Therefore, induction therapy regimens suitable for HSCT MM patients should achieve several goals: rapid disease control and strive for maximum remission; restoration of disease-related injury (e.g., renal insufficiency) as much as possible; aiming for minimal treatment side effects; reducing early disease death; and minimizing disruption of stem cell collection.
Induction therapy regimens suitable for hematopoietic stem cell transplantation should be selected based on a combination of three factors: patient status, tumor risk, and treatment regimen. Patient factors include major factors such as patient age, physical status, MM-related complications and concomitant diseases. Tumor factors include cytogenetic risk factor stratification and tumor load related to MM prognosis.Mayo Medical Center classifies active MM into high risk, intermediate risk and standard risk groups based on cytogenetic status.The high risk group is characterized by Del 17p, t(14;16) and t(14;20); the intermediate risk group by t(4;14), Del 13 and subdiploidy; the standard risk group is characterized by hyperdiploid, t(11;14), and t(6;14). MM cells with genetic abnormalities such as t(4;14) and Del 13 were poorly treated with anti-angiogenic drugs such as salbutamol, and the CR/nCR rates of salbutamol combined with dexamethasone for MM patients with t(4;14) and Del 13 abnormalities were only 8.5% and 12%, and the CR/nCR rates increased to 40% and 39%, respectively, after combining with bortezomib , but bortezomib did not improve the induction remission rate in patients with Del 17pMM. With the application of thalidomide, lenalidomide and bortezomib in recent years, the response rate of induction therapy in MM has been significantly improved, and the VGPR rate of induction therapy with early VAD and M2 regimens is less than 20%, while the VGPR rate of bortezomib combined with thalidomide and dexamethasone is nearly 70%, and the VGPR of RVD regimen with bortezomib combined with lenalidomide and dexamethasone is as high as 80%. . Since most MM patients undergo autologous HSCT, selection of induction regimens for MM patients ready for transplantation should take into account the effect of the regimen on stem cell quality in addition to patient factors, tumor characteristics and the efficacy of the regimen itself. In addition to alkylating agents such as Marfalan, which can affect stem cells, the application of the new drug lenalidomide can also have cumulative toxicity on stem cells. MM patients applying lenalidomide should preferably have their autologous stem cells collected before 6 months of initial dosing, and current clinical studies have not found significant effects of thalidomide and bortezomib on stem cell collection in MM patients. Regarding the appropriate induction regimen for MM patients undergoing HSCT, the NCCN 2010 recommendations focus on different combinations of bortezomib, dexamethasone, adriamycin, thalidomide, and lenalidomide.
Timing of Hematopoietic Stem Cell Transplantation
Fermand JP et al. reported that early transplantation with autologous hematopoietic stem cells once the patient has achieved good results with induction therapy is preferable to late transplantation after progression, although early autologous hematopoietic stem cell transplantation has a better overall survival than late transplantation. Overall survival (OS) was 64.6 months for early HSCT and 64 months for late transplanters, with no significant difference in OS between early and late transplantation; however, transplant-related mortality (TRM) was 9% for early transplantation compared to 14% for late transplanters, and survival time without symptoms and treatment-related toxicity was significantly longer for early transplanters than for late transplanters. The European Registry of Bone Marrow Transplantation (EBMT) reported [8] that patients with multiple myeloma undergoing reduced-dose allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT) had significantly better OS and progression-free survival (PFS) than patients with non-first remission transplantation if transplantation was performed in first remission. Patients with MM who underwent RIC allo-HSCT within 1 year of disease had significantly longer OS and PFS than those transplanted after 1 year of disease, and significantly lower TRM than those transplanted after 1 year of disease. Therefore, whether autologous HSCT or allogeneic HSCT is considered, it should be performed as early as possible after MM patients have controlled their disease with induction therapy.
Choice of hematopoietic stem cell transplantation modality
There are four main types of HSCT for MM: single autologous HSCT (AHSCT), double autologous HSCT (DAHSCT), single autologous HSCT sequential reduced-dose allogeneic HSCT (AHSCT + RIC allo-HCT) and clear-marrow allogeneic HSCT (MAC allo-HCT). HCT). The choice of transplantation modality should be based on various factors such as the patient’s age, physical status, tumor risk stratification, treatment response and donor status.
The single autologous HSCT IFM 90 study reported that AHSCT was significantly better than conventional dose chemotherapy alone for MM patients, both in terms of treatment response rate and OS and PFS. Therefore, AHSCT is recommended for prolonging patient survival and improving quality of life in MM patients aged 65 to 75 years or younger, who can take care of themselves and have no significant impairment in organ function. Since the depth of response after treatment in MM patients is closely related to the time to progression, some scholars have sought to increase the depth of response to treatment by increasing the pretreatment intensity of AHSCT to improve the patient’s transplantation outcome. However, Moreau P et al [9] found that mafalan combined with total body radiotherapy (TBI) in AHSCT did not increase the remission rate, and patients’ OS and EFS decreased instead. et al. also found that BU/CY, a common pretreatment regimen in other hematologic oncology transplants, also did not increase efficacy compared with Marfalan 200, and the survival rate in the BU/CY group was instead significantly lower than that of Marfalan 200. Therefore, Marfalan 200 mg/m2 has now become the accepted pretreatment regimen for AHSCT. Recent studies have shown that the combination of marfalan with bortezomib in pretreatment regimens can significantly increase the efficacy of AHSCT if patients have not experienced serious neurotoxicity and other toxic side effects during the previous application of bortezomib. Therefore, for suitable MM patients, the pretreatment regimen of AHSCT may consider Marfalan combined with bortezomib.
Double autologous HSCT The need for double autologous HSCT in MM patients suitable for AHSCT should be based on the efficacy of the first transplant. Therefore, double autologous hematopoietic stem cell transplantation (DAHSCT) was once considered the standard of care for patients with transplanted multiple myeloma. However, a stratified analysis of the efficacy of double autologous HSCT versus single autologous HSCT found that if MM patients did not achieve a very good partial response (VGPR) or better in the first transplant, they needed to be able to increase the degree of remission and gain a survival advantage in the second transplant, with 7-year OS improving from 11% in single AHSCT to 43% in DAHSCT; if MM patients achieved a VGPR in the If MM patients achieved more than VGPR in the first transplant, no further increase in remission and survival advantage could be achieved from the second transplant on demand. Subsequently, the Bologna 96 clinical study also confirmed that although the overall efficacy of DAHSCT was significantly better than that of a single autologous HSCT, MM patients who achieved nCR or CR or higher after the first transplant could not benefit from a second autologous HSCT. Therefore, since 2007, NCCN guidelines have recommended a second autologous HSCT for patients who are suitable for autologous HSCT if they did not achieve an outcome above VGPR with the first transplant, while a second autologous HSCT is not recommended after achieving an outcome above VGPR with the first transplant.Desikan KR et al [11] comparatively studied showed that increasing the intensity of pretreatment with systemic radiotherapy (TBI) or cyclophosphamide (Cy) did not improve the rate of complete remission if added to Marfalan 200 mg/m2, and instead caused a significant decrease in OS and EFS due to increased pretreatment toxicity, with median OS and EFS of 76 and 61 months in the MEL group and 25 and 15 months in the MEL+TBI group, 25 and 15 months, respectively, and 39 and 27 months, respectively, in the MEL+Cy group. Therefore, the pretreatment regimen for MM patients undergoing a second HSCT remains appropriate with Marfalan 200 mg/m2.
Single autologous HSCT sequential reduced-dose allogeneic HSCT (AHSCT +RIC allo-HCT) Although autologous HSCT is the main transplantation modality for MM patients, AHSCT does not cure MM, and patients mostly experience life-threatening disease progression within 10 years. Bruno B et al. found that for MM patients younger than 65 years of age, patients were divided into two groups according to the availability of HLA-matched sibling donors and the patients’ wishes, one group received double autologous hematopoietic stem cell transplantation (DAHSCT) and the other group received single autologous hematopoietic stem cell transplantation with a reduced pretreatment dose of HLA-matched sibling donors. There was no significant difference in TRM between the two groups, with a CR rate of 26% and PR of 63% in the DAHSCT group and a CR rate of 55% and PR of 31% in the AHSCT+RIC Allo-HSCT group; disease-related death was significantly higher in the DAHSCT group than in the AHSCT+RIC Allo-HSCT group. The median OS and EFS in the DAHSCT group were 54 and 29 months, respectively, compared with 80 and 35 months in the AHSCT+RIC Allo-HSCT group. the PETHEMA clinical study also confirmed that the CR rate was significantly higher in the AHSCT+RIC Allo-HSCT group than in the DAHSCT group, and the AHSCT+RIC Allo-HSCT group had a significantly higher CR rate than in the DAHSCT group, and the AHSCT+RIC Allo-HSCT group had a significantly higher CR rate than in the DAHSCT group. HSCT group had a significantly higher CR rate than the DAHSCT group, and the AHSCT+RIC Allo-HSCT group had a higher PFS than the DAHSCT group. The European Bone Marrow Transplant Registry (EBMT) data on MM patients undergoing RIC Allo-HSCT showed that pretreatment regimen containing maryland or anti-lymphocyte globulin (ATG) was a poor prognostic factor, and 3-year OS was significantly lower in those with pretreatment regimen of maryland than in those without maryland (18% vs 47%), and 3-year OS was significantly lower in patients with pretreatment regimen containing ATG than in those without ATG ( The pretreatment regimen for MM patients undergoing RIC Allo-HSCT was preferable to marfalan combined with fludarabine.
Clear myeloid allogeneic hematopoietic stem cell transplantation For MM patients, although the AHSCT+RIC Allo-HSCT group improved remission rates and improved survival compared with DAHSCT; disease relapse and progression rates were significantly higher after RIC Allo-HSCT transplantation compared with clear myeloid allogeneic hematopoietic stem cell transplantation (MAC Allo-HSCT) than MAC Allo-HSCT, and long-term disease-free survival was better with MAC Allo-HSCT than with RIC Allo-HSCT, while the incidence of acute and chronic GVHD was not significantly different between MAC Allo-HSCT and RIC Allo-HSCT. Compared with autologous HSCT, MAC Allo-HSCT also had a significantly lower relapse rate after transplantation than HSCT and a significantly higher PFS than the HSCT group, and of particular interest, the MAC Allo-HSCT group showed a plateau advantage in survival at 5 years after transplantation. Therefore, MAC Allo-HSCT is worth considering for relatively young age (e.g., patients under 45 years of age), tumor grouping in the high-risk poor prognosis group and the availability of HLA-compatible sibling donors. However, the transplant-related mortality (TRM) of MM patients undergoing MAC Allo-HSCT is high, with a 1-year TRM of nearly 40%. Although TRM has decreased with improvements in transplantation techniques and supportive therapy, it is still a major problem to overcome for MM patients undergoing MAC Allo-HSCT. Therefore, MAC Allo-HSCT needs to be applied to the treatment of MM with caution. For MM patients suitable for MAC Allo-HSCT, Hunter HM et al [16] reported that the pretreatment regimen Mel/TBI was superior to Cy/TBI. the CR rate in the Mel/TBI as pretreatment regimen group was 64.7% and the 5-year disease recurrence/progression rate was 36.7%, whereas the CR rate in the Cy/TBI as pretreatment regimen group was 47.2% and the 5-year disease recurrence/ progression rate of 80.8%.
Maintenance therapy after autologous hematopoietic stem cell transplantation
The TT1 clinical study showed that the median survival of patients who were able to maintain a sustained remission for 3 years after AHSCT was 6.4 years, while the median survival of those who had disease progression after achieving remission after AHSCT was only 1.8 years. Similarly, the TT2 clinical study confirmed that patients who maintained a 3-year sustained remission after AHSCT had a significantly better survival than those whose disease progressed after remission (p<0.0001). Therefore, how to keep MM patients in sustained remission after transplantation through maintenance therapy is an area of ongoing interest. Interferon has been used for maintenance therapy, but most studies have concluded that interferon as maintenance therapy does not significantly improve patient prognosis. The current drug that is more certain as a maintenance therapy is thalidomide, which significantly prolongs both the overall survival of MM patients and the duration of disease progression-free survival. More clinical studies are needed with the newer drugs lenalidomide and bortezomib as maintenance therapy drugs.
Summary
Autologous hematopoietic stem/progenitor cell transplantation is currently the main modality for MM transplantation, with significantly higher efficacy than conventional chemotherapy, while autologous hematopoietic stem cell transplantation will almost inevitably eventually result in disease relapse or progression and is not yet a means of curing MM. Although allogeneic HSCT has the theoretical potential to cure MM, transplantation-related mortality and disease recurrence remain key issues to be addressed and are limited by the source of the donor. For patients with MM who are suitable for HSCT, the maximum benefit for patients is possible only if individualized treatment procedures are selected based on evidence-based medicine and the patient’s specific situation.