Multiple myeloma (MM), also known as plasma cell myeloma, is the second most common hematological malignancy [1]. The main feature involves the aberrant expansion of plasma cells (PCs) within the bone marrow milieu, precipitating a dynamic interplay between the bone marrow microenvironment (BMM) and myeloma cells. This interaction is instrumental in triggering signal transduction cascades, thereby facilitating the pathogenesis and progression of myeloma cells, alongside promoting osteoclastogenesis and angiogenesis (Fig. 1). PCs are mature effector B cells originate from lymphoid which secrete large amounts of immunoglobulins (Ig) in response to special substance called antigens. During physiological maturation of B lymphocytes, naïve B lymphocytes in peripheral lymphoid organs are activated after receiving antigen stimulation, and then form the germinal centers to rapidly proliferate and differentiate. To cope with a variety of antigens, the proliferation process of B lymphocytes undergoes somatic hypermutation of Ig genes, and those capable of producing antibodies that bind to antigens with high affinity are eventually retained to become PCs. Long-lived PCs migrate back to the bone marrow and secret antibodies for prolonged periods of time to protect the body. In fact, the genetic polymorphism of B lymphocytes is a double-edged sword. While increasing antibody diversity, it also increases the possibility of carcinogenesis of PCs. These cancerous plasma cells migrate back to the bone marrow and accumulate to crowd out the healthy blood cells and cause hypercalcemia, renal insufficiency, anemia, and bone destruction (CRAB criteria) [2]. More than 100,000 cases have been diagnosed with MM, accounting for 1−2 % of all malignant tumors and 10 % of hematologic tumors yearly worldwide [3]. The rapidly rising morbidity of MM and common relapse makes it a major and growing medical challenge.

For the treatment of MM, alkylating agents such as melphalan (1, Fig. 2) or cyclophosphamide (2, Fig. 2); corticosteroids such as prednisolone (3, Fig. 2) or dexamethasone (4, Fig. 2); thalidomide (5, Fig. 2), and its immunomodulatory derivatives (IMiDs); the small molecule proteasome inhibitors (PIs) and the anti-CD38 antibodies, daratumumab and isatuximab, represent the most active drugs in the clinic today. While existing therapeutic options are efficacious, none are curative and resistance invariably develops. A 5-year survival has been reported at 46.6 % [4]. Thalidomide was first used for the treatment of MM in the late 1990s, and discovery of its anti-MM activity led to the rapid development of lenalidomide (6, Fig. 2) and pomalidomide (7, Fig. 2). All three IMiDs function as adaptor molecules for the E3 ligase CRL4-CRBN, altering its substrate specificity and inducing the degradation of key oncoprotein, such as IKF1 and IKF3 [5,6]. Bortezomib (8, Fig. 2), the first in class PI, was approved by the FDA for the treatment of MM in 2003. Over the past 15 years, two additional PIs, carfilzomib (9, Fig. 2) and ixazomib (10, Fig. 2), have also secured FDA approval. The monoclonal antibodies elotuzumab, daratumumab, and isatuximab have demonstrated efficacy in combination with the IMiDs and/or PIs and are in mainstream clinical usage. In addition, several other drugs with distinct mechanisms have also been approved by FDA, including the pan-histone deacetylase (HDAC) inhibitor panobinostat (11, Fig. 2), the XPO1 inhibitor selinexor (12, Fig. 2), the B-cell maturation antigen (BCMA) targeted antibody−drug conjugate (ADC), belantamab mafodotin (13, Fig. 2) [7], and the bispecific antibody Teclistamab [8]. A number of additional antibodies and immune cell engaging biologics are also in development.

Although the current treatment can effectively improve the outcomes of MM patients, the majority of MM patients will relapse repeatedly due to the acquisition of resistance. After each relapse, patients will face fewer treatment options and shorter remission duration, and will ultimately have no effective treatment regimens. Furthermore, during treatment, the lives’ quality of patients is difficult to balance due to the undesired side effects of current therapies, especially for frail elderly patients (median age at diagnosis is 70 years) [9].

The mechanism of drug resistance in MM is complex, like the disease itself [10]. The pathogenesis of MM is a complex process involving multiple mutational events such as the acquisition of hyperdiploidy, translocation involving the heavy chain gene locus, copy number abnormalities, secondary translocations, and somatic mutations [11]. Such genetic events make MM a complex heterogeneous cytogenetic disorder characterized by relapse and refractory (Table 1) [12]. For instance, the mutations in tumor suppressor genes have been connected to resistance against immunomodulatory drugs, steroids and monoclonal antibodies [13,14]. The changes of proteasome subunit expression and upregulation of the ubiquitin proteasome system (UPS) have been associated with resistance to proteasome inhibitors [15]. The mutations in the targets of drugs reduce the original binding affinities [10]. Furthermore, high levels expression of heat shock proteins in drug resistant MM cells have been found [16]. Besides, BMSCs and the associated microenvironment play a pivotal role in conferring drug resistance in MM, by facilitating cellular adhesion, activating signal transduction pathways and enhancing anti-apoptotic mechanisms, thereby diminishing the sensitivity of MM cells to chemotherapeutic agents [17].

There is an urgent need to develop novel, more effective and safer anti-MM therapies to overcome MM resistance and improve the lives’ quality of MM patients. Developing novel therapeutic classes targeting these mechanisms of resistance or drugs that circumvent existing resistance mechanisms represents appropriate strategic approach [[34], [35], [36]]. Recently, quite a few potential targets and corresponding regulators have been discovered for the treatment of MM. Herein, this review will focus on the potential targets reported recently against MM, and also summarize novel combination therapy options and targeted protein degradation therapies (Table 2).