# Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma  
[PERSON]  
1 Department of Hematology, Faculty of Medicine, Vasile Goldis Western University of Arad, Rebreanu 86, 310144 Arad, Romania1  
[PERSON]  
2*  
have bone metastases at the diagnosis, and their percentage increases to 90% during the progression of the malignancy. These patients experience bone lysis caused by inhibition of osteoblast differentiation [11]. Additionally, this condition is associated with hypercalcemia, renal failure, and anemia, which affect the quality of life as well [7,12]. In the recent years, the survival rate of MM patients has increased significantly due to the use of transplanted stem cells or new therapeutic agents, and significantly increased survival rate [13]. The main therapies used in MM are:  
Glucocorticoids as dexamethasone and prednisone are steroids used in the treatment of MM [14]. Glucocorticoids indirectly inhibit target genes through inhibitory interactions of glucocorticoid (GC)-glucocorticoid receptor (GR) monomers with NF-kB and activator protein-1 (AP-1) [15], the latter being important factors in the pathogenesis of multiple myeloma [16, 17, 18]. * Proteasome inhibitors [19, 20, 21]. The proteasome is a multicatalytic target responsible for the degradation of the proteins. To date, there are only three proteasome inhibitors approved for clinical: ixazomib [22], bortezomib [23], and carfilzomib [24]. These drugs can stimulate osteogenesis in MM patients [25]. Proteasome modulation can also be achieved by binding lenalidomide to thalidomide and acting as E3-Ligase inhibitors [26]. * DNA damaging agents. This category includes alkylating drugs, such as melphalan, or other agents, as doxorubicin, as well as histone deacetylase inhibitors such as panobinostat [27]. * Immunomodulatory drugs, such as pomalidomide and lenalidomide [28, 29, 30]. MM was one of the first tumors in which the therapeutic efficacy based on immune receptors inhibition, especially of the PD-1 axis, was evaluated in preclinical models [6]. * Monoclonal antibodies [31, 32, 33]. There are two monoclonal-based therapy approved for the treatment of MM: daratumumab (CD38 pathway) [34], and clotuzumab (targetSLAMF7 pathway) [35]. The efficacy of monoclonal antibodies is the highest, but this therapy has a high cost [6]. In 2020, the FDA approved a third monoclonal antibody for MM therapy, Sarchisa (isatuximab--irfc) in combination with pomalidomide and dexamethasone [36]. Isatuximab is a monoclonal antibody that targets the transmembrane receptor and the ecroenzyme CD38, a protein overexpressed by malignant hematological cells [37]. Isatuximab is a new MM treatment for patient's refractory to lenalidomide and proteasome inhibitor [38]. Although various pharmacological strategies for the MM clinical treatments have been developed, in most patients it eventually recurred [39]. Patients have various side effects and face the development of drug resistance [39, 40, 41]. One of the harmful side effects of MM therapy is neurotoxicity. It is often associated with chemotherapy-induced peripheral neuropathy and has symptoms such as hypersensitivity, dysaesthesia, and paresthesia [42, 43]. More than 50% of bortezomib-treated patients experienced this side effect, leading to dose reduction or treatment discontinuation [6]. All these problems highlight the need to research new therapeutic targets to improve the treatment [44, 45]. In recent years, there has been a growing interest in the development of drugs to alleviate the side effects of antineoplastic therapy and the emergence of drug resistance, through the use of biologically active compounds with low side effects and that are effective in the treatment of several cancers [46]. Bioactive compounds such as alkaloids, flavonoids, terpenoids or saponins have the ability to prevent the side effects of chemotherapeutic drugs, prolong survival and improve the quality of life of cancer patients [47, 48, 49, 50].