Multiple myeloma (MM) is a malignant clonal disease of plasma cells, characterized clinically by the production of monoclonal immunoglobulin (Ig) (usually IgG or IgA) or Ig light chains (κ or λ chains) [1]. MM is second only to non-Hodgkin’s lymphoma in the incidence of hematologic neoplasms, and statistics from the United States show that MM accounts for 13% of hematologic neoplasms and 1% of all neoplasms. MM predominates in the elderly, with a median age of 62 years for men and 61 years for women at diagnosis, and only 2% of patients are younger than 40 years old [2]. MM has a poor prognosis, with a median survival time of about 3 years with conventional chemotherapy. In recent years, new drugs including thalidomide, lenalidomide, and bortezomib have improved the response rate of treatment, but still cannot cure MM. autologous hematopoietic stem cell transplantation (ASCT) overcomes the dose-dependent toxicity and bone marrow clearance of high-dose chemotherapy, making high-dose chemotherapy and/or radiotherapy possible, and significantly improving the prognosis of patients [3]. The clinical application of ASCT for MM is currently on the increase, and this article will review the progress of ASCT for MM.
Pathophysiology and treatment of MM
Clinical and genetic evidence suggests that most MM progresses from an asymptomatic preneoplastic stage characterized by the proliferation of monoclonal plasma cells derived from postmitotic centers in the bone marrow, a disease state also known as monoclonal gammopathy of unknown significance (MGUS), with approximately 1% of MGUS transforming into MM each year [4]. It is generally believed that the pathogenesis pattern of MM is from MGUS to asymptomatic or smoldering MM, then progressing to symptomatic intramedullary MM, and finally extramedullary MM and plasma cell leukemia [5]. Because many MM patients have no clinical symptoms at the MGUS stage, clinical attention should be paid to it.
Cytogenetics
Recent research advances have shown that all MM patients have genetic abnormalities, and MM actually has persistent genetic alterations, such as duplications or deletions of different combinations of chromosomes, translocations of Ig heavy chain genes localized at 14q32.3, and intensification of Ig genes, all of which result in dysregulated gene expression [6]. Chromosomal abnormalities are closely associated with prognosis, where hyperdiploid patients generally have a better prognosis, while patients with deletions of chromosome 17p13 (incidence about 10%) or translocations of 14q32.3, 4p16.3 (incidence 15%), and 16q23 (incidence 5%) have a poorer prognosis [7]. Genetic abnormalities become more complex in later stages of the disease, such as mutations in oncogenes (including the RAS family), secondary translocations in MYC genes, and inactivation of the tumor suppressor gene p53 (see Figure 1). These genetic abnormalities are associated with disease progression, and the genetics manifest differently at different disease stages.
Drug resistance in MM
MM is resistant to most conventional chemotherapeutic agents. Because most plasma cells do not differentiate, cell cycle-specific drugs have limited effect, and alkylating agents (marfalan and cyclophosphamide) and corticosteroids are the most effective conventional chemotherapeutic agents. In addition to the lack of dividing plasma cells, several factors contribute to MM drug resistance. Interleukin 6 (IL-6) is an important survival factor for myeloma cells and induces resistance to drug-mediated apoptosis. In addition, the interaction between myeloma cells and extracellular matrix proteins as well as bone marrow mesenchymal cells, osteoblasts, osteoclasts and epithelial cells plays a key role in the pathogenesis of myeloma and drug resistance, and the interaction between myeloma cells and the bone marrow microenvironment secretes anti-apoptotic factors [8] (see Figure 2). One approach to overcome myeloma resistance is to increase the dose intensity of the drug. Because of the mild non-hematologic toxicity of mafran, high doses of sedative mafran can increase tumor cell clearance, but can lead to severe long-term myelosuppression. The high mortality and complications associated with high-dose Marfalan chemotherapy can be significantly reduced if autologous stem cells are harvested prior to Marfalan administration and then returned to the patient after administration [9]. This therapeutic regimen is known as ASCT, in which the homing of hematopoietic stem cells to the bone marrow microenvironment is an important part of the process, and the exact mechanism is still unknown, but there is evidence that stromal-cell-derived factor-1 (SDF-1) binding to CXC chemokine receptor 4 (CXCR4) on the surface of hematopoietic stem cells is an important step [4] (see Figure 3 ). ASCT itself has no antitumor effect and is only a support for high-dose chemotherapy, but it makes lethal doses of marfarin chemotherapy possible.
The mechanism of action of high-dose Marfalan is mainly the loss of DNA from tumor cells. Recently, drugs such as thalidomide, bortezomib and lenalidomide have been found to act not only on myeloma cells but also affect the bone marrow microenvironment [10], and the emergence of these drugs has provided new ideas to overcome tumor resistance.
Clinical evidence for ASCT in the treatment of MM
About 30 years ago, the combination of marfalan and prednisone (MP) became the standard regimen for the treatment of MM, but the complete remission rate (CR) of this regimen was less than 5%, and eventually all patients relapsed. Other, more complex combinations of chemotherapeutic agents have not significantly improved survival either [9]. About 25 years ago, high-dose Marfalan combined with ASCT support was used in the clinic [11]. Subsequently, the French Myeloma Collaboration (IFM) first conducted a clinical randomized controlled trial that confirmed the efficacy of ASCT over conventional chemotherapy, with patients in the ASCT group having better response rates, event-free survival time (EFS), and overall survival time (OS) than the control group [12]. 7 years later a study by the British Medical Research Council (BMRC) came up with the same results [13]. Another important finding in these studies was that ASCT significantly increased the rate of CR (defined as negative serum protein electrophoresis) and the rate of very good partial remission (VGPR, defined as a >90% decrease in M protein), and this outcome was significantly associated with prolonged disease-free progression survival (PFS) and OS. Five other randomized clinical trials also yielded similar results [14-18]. Overall, ASCT improved treatment response rates from 50-55% to 60-80%, CR and VGPR rates from less than 20% to 40-45%, and PFS from 15-20 months to 25-30 months. ASCT improved median OS from approximately 36 months to 50-55 months, regardless of whether the patient was primed or in a progressive phase. In the last decade, the application of new targeted drugs such as thalidomide, lenalidomide, and bortezomib has significantly improved MM remission rates, and these drugs are used for pre-transplantation therapy or pretreatment, which may improve response rates, reduce recurrence, and hopefully improve long-term survival.Harousseau et al [19] treated 44 patients with primary MM using bortezomib in combination with ASCT, resulting in an overall response rate 66%, including 21% CR and 10% VGPR, 4 patients with a lesser response, 6 patients with stable disease status, and 5 patients with disease progression. Although these agents have shown efficacy in the clinic, their long-term efficacy and whether they can be used as an alternative treatment to ASCT remain unknown.
Clinical application of ASCT for MM
Patient selection
It is currently believed that only symptomatic MM requires active treatment, and asymptomatic MM can be observed first because the disease state in asymptomatic MM can be maintained for several years without progression, and then there is no clear evidence that treatment improves the prognosis of these patients [20]. ASCT is indicated for patients with active MM who are relatively young in age and without severe comorbidities. The efficacy of ASCT in patients aged >65 years is controversial. A randomized controlled trial by Facon et al [21] in patients aged 65-75 years showed that the efficacy of ASCT was similar to that of the MP regimen, and both were worse than the MPT (MP+thalidomide) regimen. Secondly, ASCT is best performed in patients with good renal reserve function, generally requiring a blood creatinine <2.3 mg/dl. However, recent studies have also shown that ASCT is an effective treatment for MM patients with renal insufficiency, and Parikh et al [22] treated 46 MM patients with creatinine >2 mg/dl with ASCT, resulting in an overall response rate of 75% (including CR 22%, PR 53%) and 32% (including CR 53%). PR53%), 32% of patients had >25% increase in GFR, 3-year PFS and OS were 36% and 64%, respectively, 2 patients died within 100 days after the procedure, and 39% of patients developed grade 2-4 non-hematological toxic reactions, mainly arrhythmias, pulmonary edema and hyperbilirubinemia. The authors concluded that ASCT was not associated with increased toxicity and non-recurrence mortality (NRM) in MM patients with renal insufficiency, but rather improved renal function in patients. Again, patients proposed for ASCT must have a physical status score of less than 2 (based on the Eastern Tumor Collaborative Group criteria, see Table 1). contraindications to ASCT include mainly comorbid severe cardiac, hepatic, pulmonary and neurological disease.
Unrestricted activity, with the ability to perform all pre-disease activities
Limited heavy physical activity, but able to walk and perform light physical activities (e.g., light housework and office work)
Able to walk and care for self, but unable to perform work activities, with <50% of daily bed rest on awakening
Only limited self-care, with >50% of daily waking hours in bed
Total inability to care for oneself, bedridden all day
Death
Treatment process
After nearly 20 years of development, the treatment process of ASCT is basically defined and consists of induction therapy, stem cell collection, high-dose chemotherapy and subsequent stem cell transfusion. The whole treatment process takes about 4-6 months.
Induction therapy consists of 3-6 courses of chemotherapy to reduce tumor load and plasma cell bone marrow infiltration. Because of its hematopoietic stem cell toxicity, marfarin should be avoided during induction therapy. Dexamethasone alone or in combination with vincristine and adriamycin (VAD) has long been the standard regimen for ASCT induction therapy. Recently these regimens are being replaced by dexamethasone in combination with thalidomide, lenalidomide or bortezomib. Induction therapy requires hospitalization if administered intravenously, while oral administration can be performed on an outpatient basis with weekly blood monitoring and monthly evaluation of the patient’s response to treatment, mainly in terms of blood and urine M-protein levels.
Stem cell harvesting can be started after induction therapy is completed. Currently, the source of stem cells is almost exclusively harvested from peripheral blood because of the convenience of peripheral blood stem cell collection, the speed of postoperative hematopoietic reconstitution, and the reduction of tumor cell contamination [23]. Stem cell mobilization must be performed prior to collection to increase the number of peripheral blood stem cells, and the mobilization protocol can be performed with colony cell stimulating factor (G-CSF) alone or in combination with cyclophosphamide (CTX), with G-CSF+CTX mobilization being more effective than G-CSF alone, but causing temporary bone marrow toxicity. The effect of collection is generally judged by the number of CD34+ cells, as the number of CD34+ cells correlates significantly with the rate of stem cell implantation, especially platelet recovery. The clinical requirement is that the number of collected CD34+ cells is >2×106/kg to ensure safe stem cell implantation. After collection, the stem cells are mixed with a preserving solution prepared with dimethyl sulfoxide and stored under refrigeration.
The standard pretreatment regimen for ASCT is high-dose Marfalan (200 mg/m2), which can be administered as a single dose or in two days at a dose of 100 mg/m2, with each dose to last 30-60 minutes, supplemented with hydration and forced diuresis. Stem cell transfusion is started 48 hours after Marfalan infusion, and antihistamines, antiemetics, antipyretics and corticosteroids are given before the transfusion to prevent related side effects [24], followed by stem cell infusion by central venous catheter at a rate of 5-20 ml/min, with attention to protective isolation during the infusion, and G-CSF is routinely given after the infusion to stimulate hematopoiesis, and the patient’s severe granular deficiency period usually does not exceed 10 days. Patients must be closely monitored for vital signs during hospitalization, with general physical examination at least once a day, routine blood and renal function tests at least once every other day, and liver function tests once a week if there are no clinical symptoms. Patients should continue to be monitored after discharge, especially in patients with delayed platelet recovery requiring platelet support therapy. Patients should be evaluated for disease status 1 month after transplantation and approximately once every 3-4 months thereafter. Indicators for each evaluation should include blood and urine M-protein, with immunofixation electrophoresis, serum free light chain and bone marrow examination being performed instead for patients in whom M-protein cannot be detected.
Treatment-related side effects
The toxic side effects of induction therapy are related to the treatment regimen chosen. The main side effects of high-dose dexamethasone are infection, steroid-associated diabetes mellitus and psychiatric symptoms. the side effects of the VAD regimen are twofold: thrombosis and infection caused by central venous placement; and neurotoxicity of vincristine and granular deficiency and infection caused by adriamycin. The regimen of thalidomide or lenalidomide combined with dexamethasone increases the risk of deep vein thrombosis [25], and the main side effect of the bortezomib combined with dexamethasone regimen is peripheral neuropathy. The most significant side effect of high-dose marfalan is severe long-term myelosuppression, and the median time to severe granulomatous deficiency and thrombocytopenia is reduced to 7 days with combined ASCT [23]. Fever is a common complication in the granulomatous phase, with an incidence of about 40%, including bacteraemia in about 17% [26]. Gastrointestinal toxicities are also common, with grade 3-4 mucositis occurring in about 30% of patients. Other common side effects are alopecia and gonadal toxicity, with cardiac and pulmonary toxicity and hepatic sinusoidal vein occlusion syndrome (VOD) being rare. The mortality associated with ASCT is less than 2% in most centers [9]. Moreover, ASCT as initial therapy does not increase the incidence of secondary neoplasms, and the probability of patients developing myelodysplasia or secondary acute myeloid leukemia within 10 years is <5% [27]. The side effects associated with stem cell infusion include nausea and vomiting, headache, chills and fever [24], which are caused by two factors: cytokines released by partial cell lysis in the infusion solution and due to the toxic effects of dimethyl sulfoxide.
Advances in ASCT for MM
Double ASCT
Although the efficacy of ASCT is better than that of conventional chemotherapy, almost all patients will eventually relapse. Therefore, the concept of double or sequential ASCT treatment has been proposed to further improve the CR rate. Double ASCT means that a high-dose horse frank and stem cell infusion is given several months after the first ASCT. Three randomized controlled trials have confirmed that double ASCT increases the PFS of patients [28-30], but only patients who did not remit from the first ASCT benefited from the second ASCT. In addition, although some patients can achieve long-term remission after double ASCT, double ASCT still does not improve prognosis in high-risk patients, such as those with high β2-microglobulinemia and chromosomal analysis suggesting a poor prognosis [31].The study by Cavo et al [29] included 321 patients with newly diagnosed MM, and patients were randomized into two groups, 163 in the single ASCT group and 158 in the double ASCT group of 158 patients, with CR rates of 33% and 47% (P=0.008), median EFS of 23 and 35 months (P=0.001), and 7-year survival rates of 46% and 43% (P=0.90), respectively, between the two groups. The authors concluded that double ASCT improves CR rates but does not prolong OS and is more appropriate for patients who fail to CR with first ASCT.
Maintenance therapy after ASCT
The need for maintenance therapy after ASCT and the choice of maintenance therapy regimen are still clinically inconclusive. New targeted drugs such as thalidomide, lenalidomide and bortezomib have shown significant efficacy in induction therapy, and their efficacy in maintenance therapy has been further investigated. Two randomized controlled studies have shown that thalidomide maintenance therapy improves remission rates, PFS, and OS [32,33]. Spencer et al [33] randomized MM patients after a single ASCT into two groups, with 114 patients in the treatment group receiving 12 months of thalidomide combined with prednisone maintenance therapy and 129 patients in the control group receiving only prednisone maintenance therapy with a mean follow-up of 3 years. The 3-year PFS rates were 42% and 23% (P<0.001), and the 3-year OS rates were 86% and 75% (P=0.004) in the treatment and control groups, respectively. The main side effect of thalidomide treatment was neurotoxicity, and the incidence of thrombosis did not differ between the two groups. The findings suggest that 12 months of thalidomide combined with prednisone maintenance therapy after ASCT can prolong patient survival.
Impact of new targeted drugs on ASCT
The efficacy of new targeted drugs such as thalidomide, lenalidomide and bortezomib in induction therapy has been mentioned before, which can improve the CR rate. Another more interesting topic is how efficacious the combination of these novel agents alone is and whether it can replace ASCT in some patients. the European group performed the above-mentioned work in elderly MM patients who were not suitable for transplantation, comparing the efficacy between the MP regimen and the combination of MP plus thalidomide, lenalidomide or bortezomib. the investigators found that the remission rate and median PFS were similar to those of patients who underwent ASCT [34-36]. Researchers in the United States also evaluated the efficacy of lenalidomide plus dexamethasone as an initial treatment regimen and found remission rates of up to 70% with extended treatment or the addition of bortezomib [37,38]. However, randomized controlled trials are still needed to confirm this, especially to compare the difference in efficacy between treatment with novel drugs in combination with ASCT and drug therapy alone.
In summary: for new-onset MM patients aged <65 years with good physical status, high-dose chemotherapy combined with ASCT should be an important part of initial treatment, and the recommended regimen for pretreatment is 200 mg/m2 of mafran [39]. Whether double ASCT has better efficacy is still controversial. The use of novel targeted drugs before and after ASCT may improve the efficacy, but the optimal use regimen for these drugs is still inconclusive.The clinical application of ASCT for MM is well established, with definite efficacy and a life expectancy of more than 5 years in patients without high-risk factors, and 30% of patients may achieve long-term remission [40]. It is worth promoting in practical clinical applications.
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