Multiple myeloma (MM) is a malignant neoplasm of bone marrow plasma cells. In the past 40 years, the treatment of MM has mainly used chemotherapy, which is effective in about 70% of patients, but patients eventually develop drug resistance, and the average survival is only 2.5-3 years. In the past 10 years or so, the application of hematopoietic stem cell transplantation has provided a new way of treatment for MM. Due to the older age of onset of MM patients, the mortality rate associated with allogeneic bone marrow transplantation is high, up to 40% or more; although autologous stem cell transplantation can reduce the mortality rate associated with transplantation, the relapse rate is higher. For this reason, scholars at home and abroad are committed to finding new ways of MM treatment. 1. Bone marrow microenvironment and MM Myeloma cells are localized in the bone marrow, and the bone marrow stroma provides them with nutrition and cytokine support. The adhesion of tumor cells to bone marrow stromal cells (BMSCs) promotes the transcription and secretion of nuclear factor kB (NF-kB)-dependent IL-6 in BMSCs. IL-6 mainly regulates the growth and survival of myeloma cells and prevents drug-induced apoptosis of myeloma cells. Both myeloma cells and BMSCs secrete vascular endothelial growth factor (VEGF), and the adhesion of MM cells to BMSCs can upregulate the secretion of VEGF. cytokines secreted by MM cells, such as tumor necrosis factor (TNF-α), insulin-like growth factor-1 (IGF-1), IL-6, and VEGF, can further upregulate the secretion of IL-6 by BMSCs. Their interaction increases the secretion of several cytokines: factors that promote myeloma growth (IL-6, IGF-1, VEGF), factors that block drug-induced apoptosis (IL-6, IGF-1), factors that activate migration (VEGF), factors that promote adhesion of myeloma cells to BMSCs (TNF-α), and factors that stimulate angiogenesis (VEGF) secretion. Although TNF-α does not directly alter the growth and survival of myeloma cells, TNF-α induces upregulation of the expression of soluble intercellular adhesion factor (ICAM-1) and vascular endothelial cell adhesion molecule (VCAM-1), cell surface adhesion molecules between MM cells and BMSCs, resulting in increased adhesion of BMSCs to MM cells and induction of increased IL-6 secretion. IL-6 enhanced cell proliferation via the RAS-MAPK pathway; enhanced cell viability via the JAK-STAT pathway; blocked dexamethasone-mediated apoptosis via the activated PI3K-AKT signaling pathway; blocked the differentiation of monocytes to dendritic cells; disrupted host immunity to MM cells; and induced VEGF secretion. In addition, MM cells prevent apoptosis by linking to fibronectin, which causes the release and accumulation of cFLIPL from organelle membranes. cFLIPL competes with procasepase-8 for Fas-associated death zone proteins. With the in-depth study of its occurrence mechanism, targeted therapies have been formed to address its pathogenesis. 2. thalidomide and its derivatives Reactive stop and its derivatives for the treatment of myeloma have the following mechanisms: l) Anti-angiogenic effect: myeloma cells adhering to BMSCs upregulate vascular endothelial growth factor (VEGF) secreted by BMSCs and MM cells. VEGF not only promotes angiogenesis, but also mediates MAPK activity and enables myeloma cells to proliferate. Reactive stop can exert anti-angiogenic effect by inhibiting the expression of bFGF and VEGF or blocking the stimulation-induced MAPK signaling pathway effect of bFGF and VEGF on vascular endothelial cells or inhibiting the vascular endothelial growth factor receptor. 2) Direct killing effect on myeloma cells: Reactive stop and its analogues can directly inhibit myeloma cells and BMSCs proliferation and kill tumor cells. Reactive arrest acts as a co-stimulatory factor to stimulate the proliferation of CD4+ T cells and upregulate the expression of IFN-a and IL-2 to kill tumor cells; it can also kill tumor cells by increasing the number and function of natural killer cells (NK cells) and LAK cells. 3) Regulation of cytokine expression: Myeloma cells interact with BMSCs to trigger and induce the secretion of factors related to myeloma cell growth The secretion of factors related to proliferation, including IL-6, IL-11, IL-1β, TGFβ, TNF-α and VEGF, is associated with the growth and apoptosis of myeloma cells as well as drug resistance. Reactive arrest can regulate the expression of adhesion molecules, block the mutual adhesion of MM cells and BMSCs, and thus prevent the secretion of cytokines associated with tumor cell growth and proliferation, which can effectively interfere with the interaction between MM cells and the bone marrow microenvironment. TNF-α can activate NF-κB, which can block apoptosis through a series of related gene expression. thal/IMiDs can directly affect the production of TNF-α, reduce the activation of NF-κB and accelerate the apoptosis of MM cells.4) Immunomodulatory effects: Its immunomodulatory effects are manifested in many aspects such as the expression of some cytokines and adhesion molecules and the regulation of immune cell activity. Reactive arrest can stimulate the proliferation of CTL cells and promote the secretion of IL-2 and IFN-γ; it can also enhance the killing power of NK cells on tumor cells and enhance their antitumor activity. This may be important for overcoming tumor resistance and completely removing micro residual disease.5) Effects on myeloma cell genes: Application of gene expression profiling study found that Response Stop could affect the differential expression of 55 genes in myeloma cells, and the functions of these genes include inhibiting tumor growth, promoting apoptosis, reducing angiogenesis, decreasing vascular density, and directly inhibiting the production of monoclonal immunoglobulins and adjusting hemoglobin production. Barlogie et al. applied response arrest 200 mg/d monotherapy to 169 patients with newly diagnosed MM, slowly increasing to 800 mg/d. The efficacy rate was 37%, with most patients achieving efficacy within 6 weeks. The effective treatment was accompanied by a reduction in malignant plasma cell infiltration in the bone marrow and an increase in hemoglobin levels, with 2-year EFS and OS of 20% and 48%, respectively. 83 patients with advanced MM treated with Response Stop monotherapy were reported by IFM with an overall efficacy rate of 66%. Patients with age >60 years, longer time from diagnosis to treatment, need for red blood cell transfusion, IgA type MM, low platelet count and plasma albumin 200 mg/d) also achieved better results with low dose of Response Stop. In 12 patients with refractory relapsed MM (including 4 with plasma cell leukemia) treated with a low dose of Response Stop (median dose 175 mg/d), 5 patients (42%) achieved partial remission and an 80% decrease in M protein (63%-90%). Dimopaulos et al. reported a synergistic effect between dexamethasone and response stop in 44 patients with relapsed-resistant MM, 77% of whom were VAD-resistant. 12, d17~20 of the 1st course, and 4 days per month thereafter. As a result, 55% of patients achieved partial remission with a median remission time of 13 months, and it was also effective in those who had previously been resistant to dexamethasone chemotherapy regimen. In Spain, 22 patients with refractory and recurrent MM were treated with ThacyDex, cyclophosphamide, and dexamethasone, with progressive dosing of 800 mg/d of ThacyDex, 50 mg/d of cyclophosphamide, and 40 mg/d of dexamethasone every 3 weeks for 4 days. 13 of these patients were effective (77%), including 9 with >50% decrease in M protein. Three cases had complete remission, five cases had progression, one case of sudden death and one case of exacerbation of infection. The results suggest that the ThaCyDex regimen can be used as a treatment for patients with relapsed/refractory MM. The efficiency of thalidomide + melphalan or thalidomide + melphalan + dexamethasone for relapsed refractory MM was 82%. A clinical study of combined liposomal doxorubicin + vincristine + dexamethasone for relapsed refractory MM showed an overall effectiveness rate of 74%.