Multiple myeloma (MM) is a hematologic malignancy with osteolytic bone destruction caused by malignant clonal proliferation of plasma cells and the presence of monoclonal immunoglobulins in the serum, which in turn leads to recurrent infections, anemia, and renal impairment. The etiology of this disease is unknown so far, and genetic, environmental, chemical factors, viral infections, chronic inflammation and antigenic stimulation may be related to the development of MM [1]. In recent years, due to the widespread use of new drugs, the survival time of MM patients is significantly prolonged, and their risk of developing second tumors is gradually recognized, especially the recent phase III clinical trials suggesting that lenalidomide may increase the risk of second tumors in MM, which has triggered clinical interest in the study of risk factors for the development of second tumors in MM patients [2]. We therefore summarize the current international understanding in this area. The development of acute leukemia (AL) secondary to MM was reported as early as the 1960s: 364 patients with primary MM treated with a chemotherapy regimen based on marfalan + prednisone (MP) had 14 (3.8%) cases of AL secondary to MM, but the total number of patients with AL secondary to MM was low at that time and did not attract attention because of the low overall survival rate. In recent years numerous studies have shown that patients with MM are more likely to develop AL or myelodysplastic syndrome (MDS) than the normal population, but the exact incidence is not yet available. Although there are limited data on studies of MM and second neoplasms, most studies consider therapeutic factors as the most important factor in the development of second neoplasms [3,4]. Because of the lack of specific molecular markers for treatment-related second tumors, it is difficult to assess the impact of different treatment regimens on second tumorigenesis. In addition to treatment-related factors, MM per se factors, host factors and environmental factors may also be influential factors in second tumorigenesis. Treatment-related factors Alkylating agents Before the introduction of alkylating agents, the median survival time of MM patients was < 1 year, and in the early 1960s, marfarin was used for the treatment of MM, which led to an increasing number of patients with longer survival time. With the use of this class of drugs, follow-up series have shown that the actual incidence of AL in MM patients is 0.7%-25.0%, 100-200 times higher than in the normal population, and that continuous treatment of MM is more likely to cause AL than intermittent treatment. In a 9-year follow-up of 476 patients with MM treated with a mean of 3 years of combination therapy with Marfalan, 11 of them developed AL/MDS, which is 100 times more likely to develop AL/MDS at the same age. Some studies have suggested that the cumulative dose of alkane over 3 years is the most significant risk factor for the development of leukemia [5]. However, not all findings support the association of alkylating agent therapy with secondary AL. Finnish investigators retrospectively analyzed data from 432 MM patients with second tumors and showed that the incidence of solid tumors in patients was no different from the normal population, while non-Hodgkin's lymphoma and AL were 4.29-fold and 45.60-fold higher, respectively, but found that the dose and duration of marfarin used in the secondary AL group versus the non-secondary AL group However, the difference in the dose and duration of treatment between the secondary AL and non-secondary AL groups was not found to be statistically significant [6]. However, most scholars still believe that chemotherapy is the main factor in the development of AL after MM treatment, and the mechanism may be: (1) leading to recurrent bone marrow suppression and regeneration, making stem cell proliferation prone to clonal changes. (2) re-injuring bone marrow hematopoietic stem cells, causing their genetic aberrations or recombination, and allowing the expansion of the original clone of leukemic cells. (3) Trigger potentially leukemogenic initiating factors or activate leukemia viruses. (4) Weakening the function of the patient's immune surveillance system, losing the ability to kill and remove aberrant abnormal cells and leukemic clones, allowing the leukemic cells to continue to increase in value. (5) Feedback inhibition of differentiation and appreciation of MM cells by aberrantly appreciating leukemic cells [7]. Autologous hematopoietic stem cell transplantation (ASCT) In recent years, it has been suggested that ASCT itself is more likely to influence the development of MDS/AL than pre-transplant chemotherapy: Barlogie et al [8] reviewed 2418 MM patients who underwent ASCT between 1989 and 2007, 105 of whom had MDS-related cytogenetic Krishnan et al [9] et al. retrospectively analyzed 841 MM patients who underwent ASCT from 1989 to 2009 and showed that 60 patients presented with secondary tumors, with non-melanoma skin cancer (27), MDS and AL (9) being more common. And the incidence of secondary tumors within 10 years after ASCT was 15.7%. However, the shortcoming of these studies is that they did not analyze the chemotherapy regimens and cycles before ASCT in MM patients, and thus cannot more accurately explain the association between secondary tumors and ASCT in MM. Govinedarajan [10] et al. divided 188 patients who underwent ASCT into two groups: one group received no more than one course of alkylating agent chemotherapy before transplantation and one group received a longer course of alkylating agent chemotherapy; both groups received high-dose CTX mobilization and high-dose Marfan pretreatment. It was found that there were no cases of secondary MDS/AL in the first group at 36 months of follow-up, while seven patients in the second group had secondary MDS at 29 months of follow-up; and it was concluded that conventional chemotherapy before ASCT was a causative factor for secondary MDS/AL in MM, independent of pre-ASCT marrow clearance, post-transplant maintenance therapy and other treatments [8].In 2011 Mailankody et al [ 11] summarized data from 8740 patients with MM in Sweden between 1986 and 2005 also found no statistically significant difference in the risk of developing MDS/AML before 1995 versus after ASCT was performed in 1995, thus supporting that ASCT does not increase the risk of secondary MDS/AML in MM.A retrospective analysis of 2021 patients with MM from 1973-2008 by Razavi et al [12] also The same conclusion was reached in a retrospective analysis of 2021 patients with MM from 1973 to 2008. Thus the role of ASCT in MM secondary second tumors is not clear, rather, the above related studies suggest to some extent that conventional chemotherapy before transplantation plays a very important role in MM secondary second tumors. Thalidomide There are few studies on thalidomide and second tumors secondary to MM. the TT2 clinical study conducted by Usmani [3] et al. compared DTPACE (dexamethasone + thalidomide + cisplatin + doxorubicin + cyclophosphamide + etoposide) and DAPCE (dexamethasone + cisplatin + doxorubicin + cyclophosphamide + etoposide) chemotherapy followed by ASCT, and respectively There was no statistically significant difference in the incidence of second tumors between the two groups of patients treated with thalidomide or placebo for maintenance. In a Swedish study, MM patients were divided into two groups according to the time of marketing of thalidomide, and the results showed that there was no statistically significant risk of secondary tumors in the two groups of MM patients before and after 2000 Bortezomib SanMigue [14] et al. followed up 682 primary MM patients for up to 70 months after administration of VMP and MP6 cycles, respectively, and showed that secondary tumors were found in 6% of the VMP group and in 6% of the MP group. The results showed that 6% of the VMP group had a second tumor and 4% of the MP group had a second tumor, and the difference was not statistically significant. Bortezomib has not been found to induce second tumors in MM, but it is not known whether bortezomib can induce second tumors in MM due to the short duration of the drug's marketing and the fact that long-term follow-up data are not yet available. Lenalidomide Three randomized phase III clinical trials of lenalidomide maintenance therapy published in recent years concluded that lenalidomide maintenance therapy increases the risk of second tumors. The MM015 clinical trial group found an increased incidence of second tumors in the MPR (marfalan + prednisone + lenalidomide maintenance) group in MM patients older than 65 years of age. However, all three randomized phase III clinical trials confirmed the benefit of lenalidomide in progression-free survival in MM patients [15-18]. Other studies have also suggested that the application of lenalidomide for maintenance therapy after MM treatment may be associated with secondary second tumors [19-20]. However, related scholars have proposed the opposite view, and Pratt [21] showed by meta-analysis that the risk of developing a second tumor in MM patients after lenalidomide application is small and much lower than the mortality caused by MM proper, and pointed out that similar studies should focus more on the analysis of lenalidomide dose and maintenance duration, whether combined with other regimens and individual patient factors. The largest clinical study on secondary tumors in MM, which analyzed data from a total of 2012 patients with MM from 1973-2008, showed no significant difference in the risk of secondary tumors before and after the advent of the new drug lenalidomide (P=0.43) [12]. Therefore, lenalidomide still requires long-term follow-up to obtain more clinical data to investigate whether it can induce second tumors in MM. The mechanism of second tumorigenesis is complex, and MM factors may be relevant, but clinical data on untreated MM combined with second tumors are difficult to obtain. A large Swedish clinical study [11] analyzed data from 5652 patients with monoclonal immunoglobulinemia of undetermined significance (MGUS) who developed MDS/AML between 1986 and 2005 and found that their risk of developing MDS/AML was 8.01 times higher than that of patients with secondary second tumors, with risk factors including IgG- and IgA-type MGUS and M Salazar et al [22] showed that activation of Fibroblast Growth Factor Receptor 3 can induce MM and bladder cancer through the NF-κB signaling pathway. The Arkansas group is currently performing whole bone marrow genomic analysis, proteomic and single nucleotide polymorphism analysis in patients with second tumors after MM treatment, which will be of great clinical importance [3]. Host factors Genetic alterations play an important role in the progression and prognosis of MM patients, and studies have shown that patients with MM secondary to second tumors have decreased CD34 expression levels, but the exact mechanism is unknown, and some studies have found that MM patients with secondary MDS or MDS-related cytogenetic abnormalities have low CD34+ cell counts in stem cell collections, suggesting that the host's own bone marrow abnormalities may be associated with secondary second tumors [23]. However, the role of underlying molecular genetic heterogeneity in the development of second tumors needs to be further investigated. Gene polymorphisms can vary by up to 95% in drug accumulation and effects among MM patients, and they differ to varying degrees in encoding drug metabolism-related enzyme systems, DNA repair, and drug transport, thus making MM patients differ in their susceptibility to second tumors. In addition to the above factors, other factors can also predispose MM to secondary tumors.Razavi et al [12] analyzed risk factors in 2012 MM patients with secondary tumors from 1973 to 2008 and found that gender (more common in women), latency (median latency of 5.21 years), age (decreasing with age), and prolonged disease duration can predispose MM to secondary tumors . There is also a significant difference (P < 0.05) in the occurrence of second tumors in MM patients by race, with African Americans (19%) having a higher risk of developing second tumors [24]. The incidence of MM in China is lower than that in Europe and the United States, and MM secondary to second tumors is mostly reported on a case-by-case basis. There is a lack of similar large clinical trials, and it is uncertain whether alkylating agents and immunosuppressive therapy in MM patients develop secondary malignancies. Although alkylating agents may have the risk of inducing a second tumor, the late death caused by AL after MM chemotherapy is significantly less than the early death caused by MM without treatment, so comparing their advantages and disadvantages, alkylating agents like MTX and Marfalan should still not be abandoned as chemotherapeutic agents for MM [25]. in May 2012, the FDA approved an update of the labeling of Celgene's lenalidomide safety information, primarily to include warnings and precautions related to the increased risk of developing a second primary tumor (specifically AML, MDS, and Hodgkin's lymphoma) in patients with newly diagnosed MM treated with the drug. For this reason, the FDA requires that both physicians and patients carefully weigh the pros and cons before choosing treatment with lenalidomide. However, the FDA has not modified, adjusted, or limited the indications for lenalidomide in the treatment of multiple myeloma and continues to emphasize that "the benefits of lenalidomide treatment (in patients with newly diagnosed multiple myeloma) are believed to continue to outweigh the risk of potentially serious adverse reactions. Lenalidomide has been used for advanced solid tumors such as prostate cancer, thyroid cancer, hepatocellular carcinoma, pancreatic cancer, renal cell carcinoma, and melanoma with proven efficacy due to its anti-angiogenic effects [26]. This plays a double role for patients with MM secondary to solid tumors, not only with anti-myeloma activity but also with anti-solid tumor effects, which can be tried in clinical practice. Conclusion In conclusion, MM secondary to a second tumor is a multifactorial integrated process, and the specific pathogenesis remains to be further studied in the future. The clinical treatment of MM should integrate various factors, weigh the advantages and disadvantages and develop individualized treatment plans, in order to achieve maximum survival and minimize the incidence of second tumors in patients.