What is the bone microenvironment: Over the past decades, our understanding of MM has come a long way, especially in terms of its molecular characteristics. microRNA (miRNA) research will help us understand MM occurrence in greater depth. miRNA is a general term for a class of short non-coding protein RNAs that are involved in the post-transcriptional regulation of target genes and can appear as major regulators in a variety of physiological and pathological processes as well as in tumorigenesis. In tumors, the oncogene p53 is often inactivated by mutation or deletion. p53 acts as a potent transcription factor that can be activated under a variety of stress conditions to induce cell cycle arrest, senescence or apoptosis. Numerous reports have shown that therapeutic induction of p53 activation can be used in the treatment of hematologic malignancies, of which MM is a plasma cell malignant proliferative disease with a high morbidity and mortality rate, which develops from a benign lesion, monoclonal gammopathy of undetermined significance (MGUS). MGUS usually does not progress significantly for several years and does not require treatment. However, for unknown reasons, this benign lesion progresses to MM at a rate of approximately 1% per year, and p53 is wild-type in both MGUS and most asymptomatic MM cases. while the regulatory mechanisms of p53 have not been fully elucidated at the molecular level, its activation has been shown to inhibit tumor progression, and it is important to understand the mechanisms of p53 loss of function in MM tumor cells. It has been reported that miRNAs can be activated by p53 in trans, and others have been found to act on p53 and/or p53 regulatory pathways, thus directly and/or indirectly affecting their activity. miRNAs are positive regulators of the p53 gene, and their downregulation of expression plays a key role in the development of MM. The aberrant expression of these miRNAs in cells directly affects the effect of p53 activation and thus the development and progression of MM, and opens up new ideas for treatment. The bone marrow microenvironment plays a key role in the aggressive progression of myeloma. The core of myeloma microenvironment regulation is the interaction between myeloma cells and normal cells of the body (e.g. endothelial cells, stromal cells, osteoblasts, etc.), which is mainly achieved through soluble proteins that activate signaling pathways such as cell growth factors (MGFs) and chemokines. The IGF1 receptor (IGF1R) is not expressed in normal plasma cells but is aberrantly expressed in plasma cells of approximately 50% of newly diagnosed MM patients. IGF1 can be produced either by MM cells themselves or by osteoblasts. The cellular transduction signals generated by the tumor environment create the conditions for MM cell survival and replication, and a better understanding of this transduction signal can help in the development of better therapeutic strategies. Epigenetics refers to changes in gene expression that are heritable without changes in the nucleotide sequence of DNA. These changes play a role in the repair of genes in normal physiological phenomena. Tumor cells have genome-wide derangements at the epigenetic level, including extensive hypomethylation, promoter-specific hypermethylation, histone deacetylation, and extensive downregulation of miRNAs. Unlike genetic alterations, epigenetic changes are potentially reversible and therefore a natural choice for novel therapeutic strategies. In MM, some genes are hypermethylated and are re-expressed after the application of DNA methylation inhibitors, suggesting the reversibility of epigenetic changes. 5’Azacytidine inhibition of DNA methylation has been shown to promote apoptosis in MM cells. 5-azido-2′-deoxycytidine, known as decitabine (DAC), has also been shown to induce p21 and p38-mediated apoptosis in G1 and G2/M phases, respectively. Targeting epigenetic drugs is expected to be used not only as single agents but also in combination with conventional chemotherapeutic agents, which can act simultaneously on MM cells and the tumor microenvironment. Osteolytic bone disease is the main feature of MM, with 70-80% of patients having osteolytic damage at diagnosis, 90% of MM having osteolytic damage during the course of the disease, and 10-15% having diffuse bone loss and osteoporosis at diagnosis. Plain photography remains the gold standard for evaluating bone disease in patients with MM. In flat bones such as the skull and pelvis plain X-rays show typical defects, and in long bones the presentation can range from fan-like lesions in the endosteum to scattered small (<1 cm) osteolytic lesions, to multiple speckled shadows, to large destructive lesions. These damages are associated with nodular occupancy of bone marrow plasma cells leading to total bone damage. Osteolytic bone damage is an important condition for the diagnosis of symptomatic MM and requires treatment. However, the limitations of plain X-rays are that osteolytic damage can only be demonstrated when 30% of bone trabeculae are lost; close to 20% of patients present with normal X-rays at diagnosis and cannot be used to assess response to treatment because osteolytic damage rarely shows evidence of cure, etc. Compared to plain radiography, CT has the advantage of higher diagnostic sensitivity in detecting osteolytic changes, especially in areas not clearly visible with plain radiography, such as the scapula, ribs, and sternum, and is superior in estimating fracture risk and instability. However, the disadvantage of CT is the high radiation dose, which is 400 times higher than that of plain photography. And, it should be noted that intravenous contrast can cause severe renal insufficiency, which is more common in MM patients themselves.MRI is widely used to detect MM bone disease. MRI is more sensitive than CT in detecting osteolytic damage and provides clearer visualization; it can distinguish myeloma from normal bone marrow; it can accurately show spinal cord and/or nerve root compression, soft tissue invasion, head and neck plasmacytoma, and ischemic necrosis of the femoral head; and it is better for evaluating myocardial amyloidosis and/or soft tissue amyloid deposits. another advantage of MRI is that it can detect bone marrow infiltration. PET/CT has a sensitivity of nearly 85% and a specificity of nearly 90% in detecting myeloma involvement in multiple myeloma. Combining MRI of the spinal cord and pelvis with PET/CT, the detection rate of active myeloma is greater than 90%. PET/CT provides additional information for the evaluation of myeloma bone disease at sites that cannot be detected by MRI. Prophylactic use of bisphosphonates has become the standard of care for multiple myeloma in the last 30 years. Both chlorophosphates and pamidophosphates have been shown to significantly reduce the incidence of skeletal-related events compared to placebo and also result in a better quality of survival. When the more potent zoledronate was invented, it was shown to be as effective as standard treatment with pamidophosphate 90 mg once monthly. osteonecrosis of the jaw caused by bisphosphonates was first reported 8 years ago, which led to a revision of treatment guidelines to limit the use of bisphosphonates to patients with primary myeloma who had been treated for less than 2 years. Barenson et al. compared three doses of zoledronate (0.4 mg,2 mg,4 mg) (ZOL0.4, ZOL2, ZOL4) with pamidophosphate 90 mg (PAM90) once monthly. The results showed no statistical difference between ZOL2, ZOL4 and PAM90 in skeletal-related events or bone pain scores, but ZOL0.4 showed lower efficacy.Gimsing et al. compared PAM90 and PAM30 and found no statistical difference in their performance grading, time to first skeletal-related event, disease-free progression survival and overall survival. Morgan et al. compared chlorophosphate (1600 mg qd) and ZOL4 and found that ZOL4 was superior in terms of disease-free progression survival and overall survival; results regarding skeletal-related events have not been published. In conclusion monthly PAM30 can be considered as the safest and most effective therapeutic dose for prophylactic use of bisphosphonates. Monthly ZOL4 infusion showed higher efficacy and better quality of survival than daily oral chlorophosphates. Autologous stem cell transplantation (auto SCT) after high-dose Marfalan chemotherapy is seen as the standard of care for MM, however a significant number of patients still have relapses, such as 13q14 deletion (13q-), especially with other cytogenetic abnormalities usually with a poor prognosis, and for these patients it is necessary to seek further treatment. A prospective multicenter clinical trial compared the efficacy of high-dose Marfalan 200 mg/m2 (HD Mel) combined with low-intensity allogeneic stem cell transplantation (allo SCT) versus autologous stem cell transplantation (auto SCT) after HD mel in patients with 13q-. 199 patients were enrolled in the trial, with a median age of 53 (30-60) years and 67% being stage III patients. Of the 126 patients (63%) who underwent allo SCT, 76 received unrelated donor stem cells; the remaining 73 patients uniformly received auto SCT. patients who received allo SCT had a higher rate of complete remission (CR) (59%) than the auto SCT group (32%, p=0.03) after 1 year of treatment. Similar overall response rates were significantly higher in the allo SCT group (91% versus 86%, p=0.003). Notably, the depth of remission was independent of the presence of graft-versus-host disease (GVHD): the CR rates were 62% and 58% for II-IV GVHD and 0-I GVHD, respectively. treatment-related mortality after 2 years of allo SCT was 15/126 (11.9%). The median follow-up was 41 months in the auto SCT group and 34 months in the allo SCT group. 2-year disease-free survival was 47.7% for auto and 61.1% for allo. In particular, overall survival was better in the allo group than in the auto group in patients with high lactate dehydrogenase (LDH) and 17q deletion with 13q deletion. Although most of the allo SCT in our trial was performed with unrelated donors, treatment-related mortality was comparable to that of related donors. Over a relatively recent follow-up period, the overall survival of allo SCT was superior to that of patients who underwent auto SCT only. To investigate the risk of second primary malignancy (SPM) in patients with relapsed refractory multiple myeloma (RRMM) treated with repeat therapy with lenalidomide (LEN) and dexamethasone (DEX), investigators analyzed the incidence of SPM: in the phase III trial of MM-009/010, it was found that compared to the placebo+Dex group, the Len+Dex group had a significantly longer survival advantage. However, patients with longer survival had an increased risk of SPM. Although maintenance therapy with LEN is well tolerated, SPM may occur in some patients including AML, MDS, ALL and HD, and solid tumors. year). However, researchers in the US have re-evaluated the risk of SPM in MM-009/010 and concluded that the risk of SPM is not increased, so the advantage of treatment options for LEN in patients with RRMM remains. Bortezomib is a first-generation reversible proteasome inhibitor with high efficacy as a single agent or in combination, significantly improving survival in MM patients as a first-line treatment option. However, peripheral neuritis and dose-limiting toxicity have limited its widespread use. To improve survival in MM patients, second-generation proteasome inhibitors including Carfilzimib, salinosporamide, MLN9708, CEP18770 and ONX0912 have entered clinical trials. carfilzimib is the most effective proteasome inhibitor. In phase I clinical trials, Carfilzomib was administered at a dose of 20 mg/m2, applied on days 1 and 2 of the week for 3 weeks, with good tolerability and activity. in phase II 003 trials, Carfizomib was applied in relapsed refractory patients, with 20 mg/m2 applied on the first course and 27 mg/m2 on the second and third courses, in 266 patients with relapsed refractory MM with previous application of at least first-line therapy including bortezomib, thalidomide or lenalidomide. The median time to diagnosis was 5.4 years, and all patients had been treated with bortezomib. 44% of patients responded poorly to bortezomib, and 88% were refractory or resistant to bortezomib. These repeatedly treated patients achieved PR in 24%, MR in 34%, and SD in 69% of patients after Carfilzomb treatment. remission rates were significantly higher in patients with poor response to bortezomib compared to previous regimens (≥MR 31% vs. 28%). The mean disease-free time to progression (PFS) for all patients was 3.7 months, with better outcomes for patients who had achieved MR (8.1 months), PR (8.8 months) and VGPR (11.6 months). The median OS was 15.5 months. Patients tolerated it well, with an incidence of grade 3/4 peripheral neuropathy of only 10%. Anemia and thrombocytopenia were seen, and administration of low-dose dexamethasone prior to this drug reduced side effects. In the phase II 004 trial, patients were treated with bortezomib for relapsed refractory MM with a PR rate of 54%, including a VGPR of 29%. at this time, a median DOR has not been achieved, and similar to the 003 trial, the 004 trial was well tolerated. Similar to bortezomib, Carfilzomib is efficacious in patients with high-risk chromosomal abnormalities (del17, del13, t(4;14) or t(14;16), etc.).