Recent Advances in the Applications of Small Molecules in the Treatment of Multiple Myeloma.

1. Introduction

Multiple myeloma (MM) is a hematologic malignancy in which plasma cells proliferate abnormally in the bone marrow, resulting in excessive levels of monoclonal immunoglobulins in urine and/or blood. The disease typically is accompanied by hyper c alcemia, r enal insufficiency, a nemia, and b one pain (the so-called CRAB tetrad of symptoms), as well as propensity to infection. MM ranks 14th in incidence among all cancers and second to non-Hodgkin’s lymphoma (NHL) as a hematologic cancer [ 1 ]. According to current estimates, in 2022 MM will be diagnosed in a total of 34,470 individuals (55.4% male) and will be responsible for 12,640 (56.1% male) deaths in the U.S. [ 2 ]. The median age at diagnosis is 69 in the U.S. [ 3 ]. Globally, in 2020 there were an estimated 176,404 cases of the disease (0.9% of all cancers), accounting for 117,077 deaths (1.2% of cancer deaths) [ 4 ]. Substantial racial disparities have been noted for all stages of MM. According to available data, compared to Caucasians, the incidence rates for the disease are higher by 2.1 times in African American men and 2.6 times in African American women [ 5 ]. Updated guidelines for the diagnosis and treatment of MM are published annually by the National Comprehensive Cancer Network (NCCN) [ 6 ]. Although the cause of MM remains unknown, cytogenetic factors are known to play a role in some MM patients classified as “high risk”. Among the most frequently encountered of these anomalies are the chromosomal deletion del(17p) and the transversions t(14;16) and t(4;14) [ 7 ].

Starting in the 1950s, the standard treatment for MM consisted of alkylating agents (melphalan and/or cyclophosphamide), often in combination with corticosteroids. Autologous stem cell transplantation (ASCT) was added to the regimen beginning in the mid-1980s. Discovery of the remarkable anti-myeloma actions of thalidomide in 1999 signaled the start of a revolutionary change in the therapeutic approach to the disease as related compounds, such as lenalidomide and pomalidomide, became available soon afterward. The therapeutic landscape for MM broadened further during the first two decades of the current century with the discovery of entirely new drug classes effective against the disease: proteasome inhibitors (bortezomib), histone deacetylase inhibitors (panobinostat), and more recently, nuclear export inhibitors (selinexor). Introduction of immunotherapy as a viable approach to MM treatment began in 2015 with the approval of the monoclonal antibodies daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7) and continued into the present decade with the antibody-drug conjugate belantamab mafodotin, the bispecific teclistamab, and chimeric antibody receptor (CAR) T-cell products, such as idecabtagene vicleucel. The cumulative effect of these and related advances has raised the five-year survival rate for MM to 55% for patients diagnosed with the disease in the period 2011–2017, compared to the situation in the mid-1970s when only a quarter of those diagnosed with MM survived five years [ 8 ]. Although the advances made thus far concerning MM have been outstanding, the fact remains that MM still is considered incurable, and although treatment measures may be initially successful, patients nearly always become refractory to therapy and relapse is the result.

The successes of the past quarter-century notwithstanding, the search for new drugs to treat relapsed and/or refractory MM (RRMM) remains a high priority in the field of drug design and development. The trend toward immunologic approaches to the disease, has been complemented by the continued emphasis accorded to “small molecules”, i.e., those with molecular weights generally lower than about one kDa. The latter offer the potential for ease of cellular entry, oral effectiveness, and comparative simplicity of synthetic preparation, as well for improved cost-benefit analyses when used with immune-based drugs [ 9 , 10 ].

Although the design of small molecules intended to interfere with the interactions of far larger macromolecules, such as nucleic acid sequences or protein domains, poses substantial problems, the field of anti-cancer drug design abounds with successes in this regard, such as the development of orally effective inhibitors of tyrosine kinase, cyclin-dependent kinases, and cereblon E3 ligase. The present review is intended to provide a synopsis of the current state of small molecules intended to treat MM, with a focus on those agents currently included in active clinical trials but not yet approved by the U.S. Food and Drug Administration (FDA). The discussion is organized primarily according to the mechanisms of action or molecular/cellular targets of the included drugs.

2. Alkylating Agents

The use of alkylating agents ( Figure 1 ) in MM dates back to the late 1950s with the first reports of melphalan (Alkeran, sarcolysin, phenylalanine mustard) in the treatment of this cancer [ 11 ]. Although this picture began to change dramatically early in the current century with the introduction of anti-myeloma drugs working by other mechanisms, interest in developing new alkylating agents to treat MM has not entirely disappeared. One such example is bendamustine, which contains a reactive mustard functionality linked to a purine-like benzimidazole ring and has been approved by the FDA for chronic lymphocytic leukemia (CLL) and indolent B-cell NHL. Although this hybrid molecule is not approved in the U.S. for MM, it is licensed in Europe, under the trade name Levact, for newly diagnosed MM (NDMM).

Overexpression of aminopeptidases in MM provides the basis for the design of melflufen (melphalan flufenamide; Pepaxto), a dipeptide in which melphalan is linked to p-fluorophenylalanine ethyl ester. The highly lipophilic nature of the conjugate enables its ready passage through the cell membrane; subsequent intracellular cleavage by aminopeptidase N (CD13) releases the active alkylator, in concentrations higher than when melphalan is given alone, to cause irreversible DNA damage and consequent apoptosis in myeloma cells, especially those resistant to melphalan [ 12 ]. Melflufen in combination with dexamethasone was granted accelerated approval by the FDA in Feb. 2021 for RRMM in patients who have previously failed at least four lines of therapy, including a proteasome inhibitor, anti-CD38 mAb, and an immunomodulator [ 13 , 14 ]. Efficacy [ORR = 23.7%; median duration of response (DOR) = 4.2 months] and safety data provided in the HORIZON trial ( NCT02963493 ) served as the primary basis for the approval. Analysis of data from a phase III confirmatory study ( NCT03151811 ; OCEAN) in which RRMM patients received melflufen and pomalidomide plus dexamethasone found that the melflufen group showed superior progression-free survival (PFS) compared to the pomalidomide cohort (6.8 vs. 4.9 months) [ 15 ]. However, examination of OS data from this trial found a higher death rate (48% vs. 43%) in the melflufen group, leading the FDA in October 2021 to withdraw its approval of melflufen for use in RRMM [ 16 ].

3. Cereblon E3 Ligase Modulators

Immunomodulation as a viable treatment approach for MM owes its origin to thalidomide, first approved by the FDA for the disease in 2006. Lenalidomide (Revlimid) (2006) and pomalidomide (Pomalyst) (2015), two related derivatives of thalidomide, subsequently were approved for use in the disease. The mechanistic basis for the anti-tumor properties of this drug class has been tracked to their ability to bind to cereblon, which in turn is enabled to form a complex with three other proteins: CUL4 (cullin4), Roc1 (regulator of cullins 1), and DDB1 (DNA damage-binding protein 1), which collectively constitute cullin-4 RING E3 ligase (CRL4), an enzyme with E3 ubiquitin ligase activity. Two zinc finger transcription factors, Ikaros (IKZF1) and Aiolos (IKZF3), which are essential for myeloma cell survival, are recruited to the complex as neo-substrates, resulting in their ubiquitination and subsequent proteasomal degradation [ 17 , 18 ]. This capacity of small molecules (known as degraders or “molecular glues”), such as the thalidomide-related anti-myeloma immunomodulators (IMiDs), to hijack the specificity of E3 ubiquitin ligases to bring about targeted degradation of disease-linked proteins, in fact, has helped usher in the field of targeted protein degradation (TPD) as an entirely new and stimulating concept in drug discovery [ 19 , 20 , 21 ]. A related strategy known as proteolysis-targeting chimera (PROTAC), which generally employs a small molecule linker that bridges an E3 ubiquitin ligase and a protein targeted for degradation, represents an extension of this approach also with potential application to cancer treatment [ 22 ].

According to current NCCN guidelines [ 6 ], lenalidomide plus dexamethasone in combination with either bortezomib or daratumumab is considered the preferred primary regimen for both transplant-eligible and -ineligible patients. Interestingly, several studies have demonstrated the efficacy of pomalidomide in about one-third of myeloma patients refractory to lenalidomide [ 23 , 24 , 25 , 26 ].

In addition to thalidomide, lenalidomide, and pomalidomide, a number of other small molecule cereblon E3 ligase modulators (CELMoDs) have been developed for treatment of hematologic cancers, including MM. This group of newer oral agents ( Figure 2 ) includes iberdomide (CC-220), which has been shown to bind to cereblon with an affinity that is twenty times higher than that of either lenalidomide or pomalidomide, leading to more efficient degradation of Ikaros and Aiolos (see above) [ 27 ]. The combination of iberdomide with dexamethasone in heavily pretreated MM patients yielded ORRs of 32% (29/90; dose-escalation cohort) and 26% (28/107; dose-expansion cohort) with serious adverse events noted in 53% (57/107) of subjects ( NCT02773030 ) [ 28 ]. Avadomide (CC-122) is another glutarimide-based cereblon modulator that has broader activity than lenalidomide, possibly due to its capacity to cause deeper and faster kinetics of Aiolos degradation in myeloma cell lines [ 29 ]. Preliminary results from a phase I study of avadomide monotherapy in NHL, MM, and solid tumors found the drug to demonstrate favorable pharmacokinetics while having an acceptable tolerability and safety profile ( NCT01421524 ) [ 30 ]. Mezigdomide (CC-92480), another promising drug in this category, shows enhanced antitumor immunostimulatory activity in myeloma cell lines, including those resistant to pomalidomide and lenalidomide [ 31 ]. This agent in combination with dexamethasone and a proteasome blocker is currently included in two myeloma-based phase III clinical studies comparing its activity both with ( NCT05519085 ) and without ( NCT05552976 ) pomalidomide (see Table 1 ). Although no data have yet appeared for either of these studies, recent reports of an ongoing phase I/II trial ( NCT03374085 ) employing mezigdomide and dexamethasone showed promising efficacy with manageable toxicity in triple-refractory RRMM patients [ 32 , 33 ].

4. Proteasome Inhibitors

Protein turnover in eukaryotic cells is accomplished primarily via the ubiquitin-proteasome pathway, which is initiated by the addition of ubiquitin, a highly conserved 76-residue polypeptide, to an e-amino group on a lysine residue on the protein intended for disposal. Once linked, the ubiquitin moiety itself can be ubiquitinated several times in tandem, thus tagging the protein for delivery to the proteasome. The ubiquitination process actually comprises three separate steps: ATP-dependent activation of E1, conjugation catalyzed by E2, and finally ligation effected by E3 [ 36 ]. In contrast to E1 (two are known) and E2 (about 60 have been identified), the human genome codes for several hundred different E3s, one of which (cullin-4 RING E3 ligase or CRL4) was discussed earlier in Section 3 .

The boronic acid dipeptide bortezomib (Velcade), the first proteasome inhibitor to be studied extensively, was approved by the FDA in 2003 for MM, marking a significant turning point in the treatment of this cancer. In comparison with bortezomib, the second-generation proteasome blocker carfilzomib (Kyprolis) has demonstrated a reduced capacity to produce the peripheral neuropathy associated with bortezomib while generating more sustained and deeper patient responses, even in patients who relapse following bortezomib treatment [ 37 ]. Carfilzomib’s actions are attributed to its capacity to irreversibly block ChT-L sites as a result of ring opening of its epoxyketone structure. However, use of this agent is hampered by its tendency to produce cardiotoxicity, as demonstrated by two recent network meta-analyses of randomized clinical trials [ 38 , 39 ]. Ixazomib (Ninlaro), which like bortezomib is a boronic acid-derived peptide reversible beta-5 CT-L inhibitor, is the most recently (2015) approved anti-myeloma agent in this class. Compared to its two predecessors, ixazomib is associated with reduced risk of peripheral neuropathy while offering the distinct advantages of oral bioavailability and once-weekly dosing [ 40 ]. Acting as a prodrug, ixazomib is rapidly converted to MLN2238, which is responsible for the drug’s pharmacological properties [ 41 ] ( Figure 3 ).

The naturally occurring marizomib (salinosporamide A) is a marine-derived proteasome inhibitor that lacks the peptide-like structure common to the other members of this class. The high lipophilicity of this intravenously administered inhibitor of all three types of proteasomes enables its passage through the blood–brain barrier, making it potentially useful in extramedullary cases of myeloma involving the central nervous system. Following demonstration that marizomib synergizes with pomalidomide in myeloma cell cultures [ 42 ], a phase I trial ( NCT02103335 ) of the combination together with low-dose dexamethasone gave an ORR of 53% (19/36) in RRMM (median of four prior therapies) [ 43 ]. The same combination currently is the subject of a phase II trial ( NCT05050305 ) involving 30 MM patients with CNS involvement. TQB3602 represents another promising anti-myeloma proteasome inhibitor currently in a clinical trial ( NCT04275583 ). Although its full structure has not been disclosed, this oral agent is said to be an acridine-containing derivative of ixazomib. Two preliminary reports recently have appeared describing the safety and efficacy of TQB3602 in RRMM patients [ 44 , 45 ].

5. Deubiquitinase Inhibitors

The removal of ubiquitin tags prior to peptide cleavage occurs in the proteasomal 19S RP caps. Mammalian 19S RPs are known to contain three major types of deubiquitinases: ubiquitin-specific peptidases (USPs), ubiquitin C-terminal hydrolases (UCHs), and a zinc metalloprotease. Interest in DUB inhibitors in MM stems from reports that several of these DUBs, especially those of the USP class, are upregulated in MM and are associated with poor prognosis [ 46 ]. For example, USP7 overexpression has been linked to bortezomib resistance, and a small molecule inhibitor (P5091) of USP7 has been shown to overcome this resistance and produce apoptosis in myeloma cells [ 47 ]. A myeloma-based clinical trial ( NCT02372240 ) of VLX1570, which inhibits both USP14 and UCHL5 and showed promise in MM in preclinical work, had to be terminated due to pulmonary toxicity [ 48 , 49 ].

6. Neddylation Inhibitors

Discovery of an alternative pathway for protein degradation, which employs ubiquitin-like proteins (ULPs) and accounts for about 20% of protein loss in proteasomes, also has spurred a search for new targets. One such target is the ULP known as NEDD8 (neural precursor cell expressed developmentally downregulated-8), an 81-amino acid peptide that shares considerable homology (80%) and sequence identity (60%) with ubiquitin. Like ubiquitin, each ULP has its own series of conjugating enzymes (E1–E3). Cullin-RING (real interesting new gene) ligase, also known as NEDD8-activating enzyme (NAE), is a ubiquitin ligase subtype that catalyzes the attachment of NEDD8 (neddylation) in preparation for its linkage to a lysine residue on the target protein, a number of which are enzymes whose overexpression in several cancer types correlates with tumor progression and unfavorable patient outcomes [ 50 , 51 , 52 , 53 , 54 ]. Correlation of poor patient prognosis and elevated NEDD8 transcript levels have been noted in bortezomib-treated MM and provided impetus for the search for NAE inhibitors as potential anti-myeloma agents [ 55 ], focusing on two agents: pevonedistat (MLN4924) [ 56 ] and TAS4464 [ 57 ]. The former, which has been under study for a number of hematologic cancers, primarily MDS, was included as a single agent in a trial ( NCT00722488 ) with RRMM patients, who failed to respond [ 58 ]. A second myeloma-based trial ( NCT03770260 ) of pevonedistat in combination with ixazomib recently was suspended for unstated reasons pending a company decision, while an initial trial of TAS4464 ( NCT02978235 ) has been terminated due to drug-induced liver toxicity.

7. HDAC Inhibitors

The nucleosome, which comprises the basic organizational unit of chromatin in all eukaryotes, is an octameric structure formed by four pairs of histones (H2A, H2B, H3, and H4) with approximately 146 DNA base pairs coiled around each octameric set. The compactness of this winding is the key feature that determines DNA’s ability to access the cell’s transcriptional machinery. Tight winding (heterochromatin) tends to favor gene silencing, while gene expression is associated with more open conformations (euchromatin). Histone posttranslational modifications, such as acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and ADP ribosylation that occur primarily on lysine residues, play important roles in regulating gene expression [ 59 , 60 ]. These alterations in histone structure, together with DNA-base methylations (primarily at cytosines), constitute “epigenetics”, i.e., changes in genetic expression not due to nucleotide sequence changes. Acetylation of e-amino groups of lysine residues situated at N-termini of histone tails constitutes one of the most important of these histone modifications. By removing the positive charge on these residues, acetylation causes relaxation of the DNA-histone interaction, thereby enhancing DNA accessibility and consequent activation of transcription. Agents that promote the addition or loss of these acetyl groups via histone acetyltransferases (HATs) or histone deacetylases (HDACs), respectively, have occupied an important niche in anticancer drug research since the late 1990s [ 61 ]. In addition to core histones, HDACs are known to catalyze removal of acetylated lysines from nonhistone proteins, including p53, HSP90, tubulin, and several of those involved in cell cycle control, angiogenesis, and DNA damage repair, among other processes, resulting in defective gene expression and cellular signaling [ 62 , 63 ].

Four classes of classical HDACs, encompassing 11 canonical subtypes, are known: I (includes HDACs 1–3 and 8); IIA, (HDACs 4, 5, 7, and 9); IIB (HDACs 6 and 10), and IV (HDAC 11). Although members of all four classes are dependent on Zn +2 for activity, they differ in sequence homology, substrate specificity, and cellular distribution (Class I: nucleus; Class IIB: cytoplasm; Classes IIA and IV: nucleus and cytoplasm). A Class III, referred to as sirtuin 2 in yeast and sirtuins 1–7 in mammals, differs from the others in that its members are dependent on NAD + for activity [ 64 ].

Dysregulation of HDAC has been reported in several solid tumors and in hematological cancers, including MM, and in a number of instances overexpression has been linked to poor prognosis [ 65 , 66 , 67 ]. As a consequence, inhibitors of HDAC ( Figure 4 ) have received an abundance of attention as potential antitumor drugs [ 68 ]. Three inhibitors of all HDAC classes (pan-HDAC inhibitors)—vorinostat, belinostat, romidepsin—received FDA approval for T-cell lymphomas during the 2006–2014 period, but each failed to demonstrate any clear benefit as a single agent in MM. Of the three, only vorinostat has been the subject of several trials in combination with established anti-myeloma agents ( Table 2 ). In the most extensive of these studies reported to date, the combination of vorinostat and bortezomib in RRMM patients produced a median PFS advantage of 0.8 months (7.63 vs 6.83) over bortezomib + placebo, although the relevance of this difference was not clear due to treatment schedule differences between the two cohorts ( NCT00773747 ) [ 69 ]. In 2015, another pan-HDAC blocker, panobinostat, was granted accelerated approval for RRMM based on the results of the phase III PANORAMA-1 study ( NCT01023308 ) in which its addition to a bortezomib/dexamethasone regimen provided a PFS benefit of 7.8 months [ 70 ]. This approval was accompanied by a required warning regarding the drug’s increased risk of potentially fatal cardiac toxicity and severe diarrhea, as revealed in the PANORAMA-1 trial. However, the drug’s sponsor failed to conduct the required post-approval studies, and in Nov. 2021 the drug’s approval was withdrawn. Additionally, preliminary RRMM patient data have begun to appear for single-agent bisthianostat, another oral pan-HDAC blocker ( NCT03618602 ) [ 71 , 72 ]. In the meantime, second-generation orally active isotype-selective HDAC blockers have risen to a position of prominence. Foremost among these are the HDAC6 inhibitors ricolinostat (ACY-1215) and citarinostat (ACY-241), as well as tucidinostat (chidamide), which targets HDACs 1, 2, 3, and 10 ( Table 3 ). The chemistry of the latter differs from that of most other HDAC inhibitors in that it lacks the zinc-binding hydroxamate group. Results of studies with citarinostat in MM have yet to be reported, but two phase Ib RRMM studies of ricolinostat revealed ORRs, respectively, of 37% when combined with bortezomib/dexamethasone ( NCT01323751 ) [ 73 ] and 55% in combination with lenalidomide/dexamethasone ( NCT01583283 ) [ 74 ]. However, neither of these trials contained a control arm, making comparison with established regimens difficult. Early results from a small study ( n = 11) of transplant-ineligible MM patients in which tucidinostat was added to a bortezomib-lenalidomide-dexamethasone (VRd) regimen reported an ORR of 90.9% compared to 100% for VRd alone. Patients in the study group were found to experience more adverse events than those in the VRd control [ 75 ].

8. Bromodomain Inhibitors

In addition to their major influence on chromatin architecture, lysine acetylation marks on histones are now known to play more complex and diverse roles in transcription regulation. Importantly, transcription factors bearing a bromodomain (BRD) have the capacity to recognize (“read”) and be recruited to these acetylation sites. Bromodomains, highly conserved structural modules of approximately 110 amino acids, facilitate interactions, that often are transient, within transcriptional complexes to impact the epigenetic regulation of gene transcription. The human genome contains 61 different bromodomains arranged in eight subgroups according to structural and sequence similarities [ 86 ]. One of these groups, the BRD and extra-terminal (BET) family, is distinguished by the presence of two N-terminal BRDs and includes as its major members BRD2, BRD3, BRD4, and the testis-specific BRDT. In recent years, BRD4 has been identified as the major BRD involved in oncogenesis and consequently has been the focus of several anti-cancer drug discovery efforts [ 87 , 88 ]. Among the cancer-associated proteins whose expression is downregulated by small molecule BRD4 inhibitors are the oncogenic driver c-Myc [ 89 , 90 ], the anti-apoptotic Bcl2 [ 91 ], and cell cycle regulators such as the cyclin-dependent kinases [ 92 ]. In particular, c-Myc has been shown to be activated in as many as 50% of MM patients [ 93 ], and in preclinical work, JQ1, a BRD4 inhibitor, demonstrated anti-myeloma activity associated with cellular senescence and cell cycle arrest [ 90 , 94 ]. However, in a phase I dosing trial that also included lymphoma patients ( NCT01713582 ), birabresib (OTX015) [ 95 ], a close structural relative of JQ1, showed no activity in a group of 12 MM patients [ 96 ]. Phase I myeloma-based studies of two other members of the BET family—RO6870810 ( NCT03068351 ) and pelabresib (CPI-0610) [ 97 ] ( NCT02157636 )—have been completed. In the former study, a cohort of 24 RRMM patients showed a low response rate with a high rate of thrombocytopenia and anemia over a range of dosages when used as monotherapy [ 98 ]. No data have appeared yet concerning responses of RRMM patients to pelabresib, although a preclinical study of this drug indicated potential synergy with lenalidomide [ 99 ].

9. Apoptosis Inducers: Bcl2, IAP, and Mcl-1 Inhibitors

The capacity of cancer cells to evade apoptosis constitutes one of their major mechanisms of survival. The apoptotic machinery encompasses two basic pathways, extrinsic and intrinsic, each with its own ability to upregulate different sets of mediators that eventuate in cell death. The extrinsic pathway is initiated by external ligands that bind to cell surface death receptors, primarily members of the tumor necrosis factor (TNF) superfamily, resulting in downstream events including activation of caspase-8, a critical mediator of apoptosis. Members of the Bcl2 family of proteins, the primary regulators of the intrinsic pathway, may possess either pro-death or pro-survival properties. Each works by heterodimerizing with members having the opposite attribute, resulting in neutralization. The conserved Bcl2 homology (BH) death domains, numbered BH 1–4, are critical components found in both pro- and anti-apoptotic members. The major pro-apoptotic members are Bax and Bak, which contain only BH3 domains, while Bcl2 itself (the founding member), Bcl-xL (B-cell lymphoma-extra large), and Mcl-1 (myeloid cell leukemia-1) are anti-apoptotic proteins that may contain any one of the four BH domains. In recent years, there has been much interest in discovering small molecule BH3-selective mimetics having the ability to block the interactions between these mutually antagonizing types of proteins to affect cancer cell death [ 100 , 101 ]. The first compound to emerge successfully from these studies was the orally bioavailable venetoclax (Venclexta, ABT-199) [ 102 , 103 ], which initially received FDA approval in 2016 for use in CLL with 17p deletion, since expanded to include acute myeloid leukemia (AML). Currently, there are two phase III studies: NCT02755597 (BELLINI) and NCT03539744 (CANOVA) investigating the potential of venetoclax in RRMM. The recently concluded BELLINI trial demonstrated that addition of venetoclax to a bortezomib-dexamethasone regimen resulted in significant improvement in PFS compared to the cohort receiving placebo (23.4 months vs. 11.4 months). Significantly, the greatest improvement in PFS was seen in patients having either t(11;14) (36.8 months vs. 9.3 months) or high Bcl2 (30.1 vs 9.9 months). However, increased mortality, primarily due to heightened infection rates, in the study group compared to placebo (7% vs. 2%) was a concern [ 104 ] and caused temporary holds, later lifted, to be placed on both phase III studies. Other studies, although in earlier phases and smaller enrollments, ( Table 4 ), have tended to substantiate the efficacy of venetoclax in t(11;14) RRMM. Results from the CANOVA trial (venetoclax plus dexamethasone vs. pomalidomide plus dexamethasone), which includes only t(11;14) RRMM patients and a planned patient size of 244, have yet to be reported but should throw important light on the future role of venetoclax in this biomarker-based MM patient group [ 105 ]. Meanwhile, lisaftoclax (APG-2575), another Bcl2 inhibitor, recently entered an RRMM trial both as a single agent and in a lenalidomide/dexamethasone combination ( NCT04674514 ) [ 106 ]. Furthermore, recruitment recently began for an RRMM study using the highly selective Bcl2 blocker BGB-11417 [ 107 ] as both monotherapy and in different combinations with dexamethasone and carfilzomib ( NCT04973605 ). A preliminary safety study has been published on a cohort of 10 t(11;14)-positive RRMM patients in this trial, indicating that the combination of BGB-11417 with dexamethasone generally is well-tolerated [ 108 ].

The aforementioned anti-apoptotic Mcl-1 recently has emerged as a druggable target for treatment of hematologic cancers [ 109 ]. The most promising agent in this space is tapotoclax (AMG176) ( Figure 5 ) ( NCT02675452 ). A preliminary report on 26 RRMM subjects (median of five prior lines of therapy) who received tapotoclax intravenously indicated that 22 patients discontinued therapy due to disease progression and that treatment-related adverse events (hematologic and gastrointestinal) were noted in all but one patient [ 110 ]. Other Mcl-1 inhibitors under active consideration for use in RRMM as well as other hematologic cancers include S-64315/MIK665 ( NCT02992483 ) [ 111 ], PRT1419 ( NCT04543305 ) [ 112 ], and AZD-5991 ( NCT03218683 ) [ 113 ].

Note should also be made of the pan-Bcl2 inhibitor R-(-)-gossypol (AT-101), an orally bioavailable polyphenol derived from the cotton plant, which has been investigated in several cancers [ 114 ] and is presently under study for RRMM in combination with lenalidomide and dexamethasone ( NCT02697344 ). An initial report on 10 subjects in this trial indicated that a Bcl2 inhibitor-immunomodulator regimen demonstrates clinical activity (ORR = 40%) with an acceptable toxicity profile [ 115 ].

For a full discussion of the current status of Bcl2 and Mcl-1 small molecule inhibitors in MM, the reader is referred to the recent review by Parrondo et al. [ 116 ]

10. Kinesin Spindle Protein Inhibitors

Eg5, a member of the kinesin-5 family of spindle microtubule-associated proteins, plays a key role in cell division by providing the mechanical energy, via ATP hydrolysis, needed for centrosome separation and bipolar spindle assembly during mitosis. Inhibition of Eg5, also known as kinesin spindle protein (KSP), causes formation of a monopolar (instead of the normal bipolar) spindle, resulting in mitotic cell cycle arrest at the spindle checkpoint and consequent apoptosis [ 123 ]. Since KSP inhibitors block mitosis without directly affecting microtubules, they may offer an advantage by avoiding the peripheral neurotoxicity seen with antitumor drugs, such as the vinca alkaloids and taxanes, which act directly on microtubules. Preclinical studies uncovered filanesib (ARRY-520) ( Figure 6 A) as a highly potent and selective KSP inhibitor [ 124 , 125 ]. Encouraging ORR data were obtained in RRMM patients in an initial trial ( NCT00821249 ) with filanesib as a single agent (16%; 5/31) and in combination with dexamethasone (15%; 8/54) [ 126 ]. A subsequent study ( NCT01248923 ) reported an ORR of 42% (8/19) in a well-tolerated regimen of filanesib with bortezomib and dexamethasone [ 127 ]. Moreover, this latter combination recently has shown encouraging activity in high-risk RRMM patients with the t(11;14) aberration [ 128 ]. Especially noteworthy is the efficacy (ORR = 45%) that this combination demonstrated in a subset of 11 patients harboring the 1q21 gain high-risk cytogenetic abnormality, a biomarker that other studies have shown to be associated with poor outcomes with daratumumab and standard triplet regimens [ 129 , 130 , 131 ]. A trial of another proteasome inhibitor, carfilzomib, with filanesib, and dexamethasone ( NCT01372540 ) was found to produce only marginal clinical benefit (ORR 37%, median PFS 4.8 months, and median OS 24.9 months), although no biomarker-based stratification was included in this phase I unrandomized study [ 132 ]. An RRMM-based study ( NCT02384083 ) of filanesib with a pomalidomide/dexamethasone regimen found a median PFS of 7 months with an OS of 19 months and substantial hematological toxicity [ 133 ]. Alpha 1-acid glycoprotein (AAG), a protein whose elevation has been found in NDMM patients [ 134 ], appears to play an important prognostic role in filanesib therapy, as first reported in a preclinical study [ 135 ]. Data reported in several of the trials shown in Table 5 have tended to confirm linkage of high plasma AAG levels to poor clinical responses to the drug, likely due to the ability of plasma AAG to sequester filanesib, effectively reducing its blood concentration to subtherapeutic levels [ 136 ].

11. Exportin Inhibitors

Transport of RNA and proteins both out of and into the nucleus is controlled by the nuclear pore complex (NPC), a large cylindrical multiprotein complex whose detailed architecture recently has been reported [ 139 , 140 ]. Although small molecules are able to diffuse passively through the NPC, macromolecules (larger than 30–60 kDa) require a nuclear transport receptor to enable nucleocytoplasmic shuttling. Such receptors are members of the karyopherin-b superfamily and are of two major types: exportins and importins. Exportin 1 (XPO1, originally known as chromosomal region maintenance 1), one of the best characterized members of the former group, is responsible for transporting a wide range of proteins (over 200 are known), including tumor suppressor proteins, transcription factors, cell cycle regulators, as well as mRNA transcripts, from the nucleus into the cytoplasm. Overexpression of XPO1 has been associated with poor outcomes in terms of OS and PFS in several cancers [ 141 ], including hematologic malignancies such as MM [ 142 , 143 ]. The validity of XPO1 as a therapeutic target for MM was confirmed in a number of reports, including genome-wide studies [ 144 ], and led to the discovery and eventual approval of the orally effective XPO1 blocker selinexor (Xpovio) ( Figure 6 B) for the treatment of MM. Like other members of this drug class, sometimes referred to as selective inhibitors of nuclear export (SINE), selinexor slowly forms a covalent bond with cysteine 528 in the nuclear export cargo-binding pocket of XPO1 [ 145 ]. Selinexor was first approved by the FDA in 2019 for use with low-dose dexamethasone for the treatment of RRMM in patients who had received at least four prior therapies [ 146 ]. Approval was granted on an accelerated basis predicated on the response rates and toxicity data obtained in the STORM trial ( NCT02336815 ) [ 147 ]. The results of a confirmatory trial ( NCT03110562 ; BOSTON) in which selinexor was combined with bortezomib and dexamethasone led in the following year to approval for use in even earlier stages of the disease, i.e., after at least one prior therapy [ 148 , 149 , 150 ]. In order to lessen the development of severe adverse effects (thrombocytopenia, neutropenia, gastrointestinal and neurological toxicity, hyponatremia), the selinexor-bortezomib-dexamethasone combination is administered on a once-weekly basis. Current trials that include selinexor in RRMM are shown in Table 6 . In a phase I study ( NCT02649790 ), eltanexor (KPT-8602) ( Figure 6 B), a second-generation oral XPO1 blocker, demonstrated improved efficacy and tolerability over selinexor when combined with dexamethasone in RRMM [ 151 ].

12. MDM2 Blockers

The tumor suppressor gene TP53 and its protein product p53 have been widely studied for their roles in a wide number of cellular responses to stress, including hypoxia, DNA damage, oncogene activation, cell cycle arrest, and apoptosis [ 166 ]. The highly complex actions of p53 appear to be most important in modulating the transcription of hundreds of genes involved in normal cellular homeostasis. Often referred to as “Guardian of the Genome”, TP53 is found to be mutated in 50–60% of all human cancers [ 167 ]. Moreover, p53 also is known to play a role in a number of processes apparently unrelated to its transcriptional activities [ 168 ]. Deletion of the TP53 locus on chromosome 17p is one of the most commonly noted genetic aberrations associated with high-risk MM, being found in 8% of NDMM patients but rising to as high as 45% upon relapse [ 169 ].

MDM2 (murine double minute 2) is one of the most widely studied p53-controlling effectors in the cell and is known to regulate p53 through two major mechanisms. First, acting as an E3-ubiquitin-protein ligase, MDM2 promotes p53 ubiquitination, marking it for proteasomal degradation [ 170 ]. Second, MDM2 binds to the p53 N-terminal domain, inhibiting p53′s capacity to effect transcription [ 171 ]. MM is one of several cancers in which MDM2 is upregulated, making it a prime target for new anti-myeloma drug development [ 172 ].

Currently, two oral agents classed as MDM2 inhibitors are in active clinical trials exploring potential synergy with proteasome inhibitors for RRMM: idasanutlin (RG7388, RO 5503781) [ 173 ] and navtemadlin (AMG-232, KRT-232) ( Figure 6 C) [ 174 ]. The first is under investigation in a small trial ( NCT02633059 ; n = 12) with ixazomib and dexamethasone limited to patients with 17p deletion, while the latter is included in a phase I dose-escalation study ( NCT03031730 ; n = 40) in combination with carfilzomib, lenalidomide, and dexamethasone. Although no data have been reported to date for either trial, it should be noted that navtemadlin has been part of a recently completed phase I study that included patients with MM and advanced solid tumors ( NCT01723020 ; N = 107). An initial report found the drug to exhibit an acceptable safety profile, although data on antitumor efficacy was very limited [ 175 ].

13. Kinase Inhibitors

13.1. Bruton’s Tyrosine Kinase Inhibitors

Bruton’s tyrosine kinase (BTK) is a non-receptor kinase belonging to the TEC family that plays a major role in B-cell development [ 176 ]. It also is expressed in T cells and NK cells where it is an important contributor to their activation as well [ 177 , 178 ]. The oral irreversible (by virtue of its covalent binding to Cys-481 in the ATP binding pocket) BTK inhibitor ibrutinib ( Figure 7 ), which has been approved for the treatment of CLL, mantle cell lymphoma (MCL), and Waldenstrom’s macroglobulinemia among others, also has been studied for possible application in MM owing to reports of robust expression of BTK in myeloma cells [ 179 ].

In a phase II trial ( NCT01478581 ), ibrutinib provided only modest efficacy when used alone or in combination with dexamethasone in 69 RRMM patients [ 180 ]. Combinations of ibrutinib with proteasome inhibitors also have been investigated based on potential synergy noted in preclinical work. Enrollment in one such trial ( NCT02902965 ) that included bortezomib/dexamethasone was suspended and eventually terminated when an increase in serious and fatal infections was noted in the study group, thus making attainment of the study’s target PFS unlikely [ 181 ]. In this connection, it is noteworthy that opportunistic infections have been reported as a significant risk in a number of ibrutinib-based studies [ 182 , 183 ]. A phase I/II study ( NCT01962792 ) of ibrutinib plus carfilzomib/dexamethasone showed median PFS and OS of 7.4 months and 35.9 months, respectively, in 59 heavily pretreated (median of three prior treatments) MM patients. While 18 (31%) of the patients in this study experienced upper respiratory infections, most were of grade 1 or 2 and none were fatal [ 184 ].

Ibrutinib also has been combined with lenalidomide/dexamethasone in a recently reported phase I dose-escalation study of 15 RRMM subjects who had received a median of four prior therapies ( NCT03015792 ). Initial results reported a median PFS of 3.8 months and, although only one patient attained a partial response (ORR, 7%), clinical benefit as defined by the trial criteria was realized in 12 of the patients (80%). Overall, hematologic adverse effects (≥grade 3) were noted in 20% of the study participants (99675) [ 185 ].

Acalabrutinib, a second-generation oral irreversible BTK inhibitor, approved by the FDA for both MCL and CLL, was the subject of a now-completed phase Ib trial for RRMM ( NCT02211014 ). The trial consisted of two arms: acalabrutinib alone ( n = 13) and with dexamethasone ( n = 14). No efficacy was demonstrated in either cohort, while serious adverse events were recorded in 38% and 64%, respectively, of the participants.

13.2. Transforming Growth Factor Receptor Inhibitors

The transforming growth factor (TGF)-b is a cytokine which effects diverse cellular processes, including growth, differentiation, migration, and cell death. The membrane-bound receptor for TGF-b contains a C-terminal domain possessing serine/threonine kinase activity. Activation of the TGF-b receptor causes phosphorylation of Smads, which in turn translocate to the nucleus where they bind to specific DNA sequences to regulate transcription of target genes [ 186 ].

The observation that MM cells demonstrate increased secretion of TGF-b linked to impaired immune surveillance and catabolic bone remodeling [ 187 ] led to a phase Ib trial ( NCT03143985 ) of the TGF-b blocker vactosertib and pomalidomide in RRMM. Initial data on 15 patients in this study, conducted without inclusion of steroids, showed that disease progression occurred in only three subjects, while the rest experienced some degree of progression-free benefit. Adverse events were reported as manageable [ 188 ].

13.3. Raf-Mek-Erk Pathway Inhibitors

The Ras gene is known to be the most frequently mutated oncogene in cancer, being found in approximately 19% of all malignancies [ 189 ]. The prevalence of Ras mutations, primarily as KRAS and NRAS, in NDMM has been estimated in one study as about 46%, rising to 64% in RRMM [ 190 ]. Such mutations manifest as increased sequential activation of the three serine/threonine protein kinases that together constitute the Raf/Mek/Erk (MAPK) downstream intracellular signaling pathway. V600E/K mutations of the Raf family member BRAF are frequently found in melanoma and other solid tumor types for which the MAPK blocking agents dabrafenib and trametinib, inhibitors of BRAF and Mek, respectively, are used clinically in combination. In addition, this mutation, which is associated with poor prognosis, is found in 2–4% of NDMM patients and about 8% in the RRMM setting [ 190 ]. Dabrafenib and trametinib, both in combination and separately, currently are under investigation in RRMM ( NCT03091257 ), as is encorafenib (anti-BRAF) with binimetinib (anti-Mek) ( NCT02834364 ; BIRMA). Although no results have been reported from either study, data are available from another trial that included the Mek inhibitor cobimetinib, which despite lacking single-agent activity, demonstrated potential but limited anti-myeloma efficacy when used together with venetoclax and/or atezolizumab ( NCT03312530 ) [ 191 ]. Vemurafanib, another BRAF blocker, whether employed alone [ 192 ] or with cobimetinib [ 193 ], has been reported to elicit some partial responses in V600E RRMM as recorded in case reports, as well as in a small cohort of patients in another trial ( NCT01524978 ) [ 194 ].

13.4. PI3K-Akt-mTOR Pathway Inhibitors

Another signaling pathway that operates downstream of Ras, the PI3K-Akt (protein kinase B)-mTOR (mammalian target of rapamycin) route, has received some attention in the search for new targets to treat RRMM but with largely disappointing results [ 195 ]. For example, the Akt inhibitor perifosine, which showed initial promise against MM in preclinical and early patient studies, failed to live up to expectations in a subsequent discontinued phase III study [ 196 ]. Trials combining the Mek blocker trametinib with Akt inhibitors afuresertib (GSK2110183) ( NCT01476137 ) or uprosertib (GSK2141795) (NCT01951495) generally have yielded modest results [ 197 , 198 ], while data have yet to be reported from an ongoing trial ( NCT02144038 ) of the oral PI3K inhibitor alpelisib (BYL719) with LGH447, a Pim blocker. The major mTOR inhibitors, everolimus and temsirolimus, have fared poorly as single agents in MM trials [ 199 , 200 ], while the few myeloma-based trials that have included mTOR blockers in various combinations heretofore have not produced published results.

14. Conclusions

Therapeutic measures to treat MM were solely dependent on alkylating agents and corticosteroids beginning in the mid-1960s. A remarkable transformation in the treatment of the disease began to occur in the 1990s as a result of two landmark discoveries: the beneficial effects of ASCT and the anti-myeloma properties of the once-banned drug thalidomide. Momentum for uncovering novel therapeutic strategies to treat this cancer continued to build with the dawn of the current century and the discovery of the proteasome blocker bortezomib and the thalidomide derivatives lenalidomide and pomalidomide, and more recently, the influx of immunologic-based therapies directed against the myeloma cell-specific surface biomarkers CD38 and BCMA. The cumulative positive impact of these developments is evident when one considers that the five-year survival rate for MM has more than doubled over the past six decades and today exceeds 50%. However, these successes are tempered by the fact that most MM patients become refractory to whatever measure is employed and eventually experience relapse.

This review focused on the continuing search for small molecules, especially those with oral bioavailability, whose addition to the armamentarium of anti-myeloma agents heretofore has proven to be complementary to ASCT and immunotherapies. Particularly noteworthy from the standpoint of new drug discovery are two recent developments that may bear future fruit as platforms for drug design based on artificial intelligence, not only for MM but for other tumors as well. One is the recent atomic-level description of the nuclear pore complex, which controls the cytoplasmic/nuclear transfer of key cancer-linked molecules, such as oncoproteins and tumor suppressor proteins. In this regard, the recently introduced exportin blocking anti-myeloma agent selinexor may portend future advances in which anticancer drugs are exquisitely tailored to affect this critical transport process. The second is the recent upsurge of work in the targeted protein degradation field as noted in Section 3 . As far as MM is concerned, while this approach as presently applied to MM targets the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), it should be applicable in principle to a wide variety of proteins on which initiation and proliferation of MM depend.

The remarkable ability of the small molecules described in this review to elicit reasonably good objective responses and PFS data with manageable toxicity in patients classed both as NDMM and RRMM has been a marked advance in cancer therapy in recent decades. However, the pathway forward poses substantial challenges, as the problem of eventual resistance to therapy will doubtless continue as a major issue. Nevertheless, if the advances made in the past few decades are any indication, the years ahead hold promise for the introduction of new orally efficacious therapeutic options with the capacity to improve the quality of life for patients afflicted with this relentless disease.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

References

1. Munshi N.C. Longo D.L. Anderson K.C. Plasma cell disorders Harrison’s Principles of Internal Medicine 21st ed. Loscalzo J. Fauci A. Kasper D. Hauser S. Longo D. Jameson J.L. McGraw-Hill Education New York, NY, USA 2022 1 22

2. Siegel R.L. Miller K.D. Fuchs H.E. Jemal A. Cancer statistics, 2022 CA Cancer J. Clin. 2022 72 7 33 10.3322/caac.21708 35020204

3. Padala S.A. Barsouk A. Barsouk A. Rawla P. Vakiti A. Kolhe R. Kota V. Ajebo G.H. Epidemiology, staging, and management of multiple myeloma Med. Sci. 2021 9 3 10.3390/medsci9010003 33498356 PMC7838784

4. Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J. Clin. 2021 71 209 249 10.3322/caac.21660 33538338

5. DeSantis C.E. Miller K.D. Goding Sauer A. Jemal A. Siegel R.L. Cancer statistics for African Americans, 2019 CA Cancer J. Clin. 2019 69 211 233 10.3322/caac.21555 30762872

6. Callander N.S. Baljevic M. Adekola K. Anderson L.D. Campagnaro E. Castillo J.J. Costello C. Devarakonda S. Elsedawy N. Faiman M. NCCN guidelines ® insights: Multiple myeloma, version 3.2022 J. Natl. Compr. Cancer Netw. 2022 20 8 19 10.6004/jnccn.2022.0002 34991075

7. Chan H.S. Chen C.I. Reece D.E. Current review on high-risk multiple myeloma Curr. Hematol. Malig. Rep. 2017 12 96 108 10.1007/s11899-017-0368-z 28317082

8. National Cancer Institute SEER Cancer Statistics Review (CSR) 1975–2017: Myeloma National Cancer Institute Bethesda, MD, USA 2020

9. Yamamoto C. Minakata D. Koyama S. Sekiguchi K. Fukui Y. Murahashi R. Nakashima H. Matsuoka S. Ikeda T. Kawaguchi S.I. Daratumumab in first-line is cost-effective in transplant-eligible newly diagnosed myeloma patients Blood 2022 140 594 607 10.1182/blood.2021015220 35580269 PMC9373013

10. Blommestein H.M. Zweegman S. Cost-effectiveness: Maximizing impact by meticulous data Blood 2022 140 525 526 10.1182/blood.2022016958 35951343

11. Blokhin N. Larionov L. Perevodchikova N. Chebotareva L. Merkulova N. Clinical experiences with sarcolysin in neoplastic diseases Ann. N. Y. Acad. Sci. 1958 68 1128 1132 10.1111/j.1749-6632.1958.tb42675.x 13627766

12. Ray A. Ravillah D. Das D.S. Song Y. Nordstrom E. Gullbo J. Richardson P.G. Chauhan D. Anderson K.C. A novel alkylating agent melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells Br. J. Haematol. 2016 174 397 409 10.1111/bjh.14065 27098276 PMC4961600

13. Holstein S.A. Hillengass J. McCarthy P.L. Melflufen: A next-generation nitrogen mustard J. Clin. Oncol. 2021 39 836 839 10.1200/JCO.20.03326 33439689

14. Schjesvold F.H. Bakker N.A. Sonneveld P. Authors’ reply: Perspective: The approval and withdrawal of melphalan flufenamide (melflufen): Implications for the state of the FDA Transl. Oncol. 2022 25 101528 10.1016/j.tranon.2022.101528 36087383 PMC9468451

15. Schjesvold F.H. Dimopoulos M.A. Delimpasi S. Robak P. Coriu D. Legiec W. Pour L. Špička I. Masszi T. Doronin V. Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): A randomised, head-to-head, open-label, phase 3 study Lancet Haematol. 2022 9 e98 e110 10.1016/S2352-3026(21)00381-1 35032434

16. Olivier T. Prasad V. The approval and withdrawal of melphalan flufenamide (melflufen): Implications for the state of the FDA Transl. Oncol. 2022 18 101374 10.1016/j.tranon.2022.101374 35196605 PMC8866737

17. Kronke J. Hurst S.N. Ebert B.L. Lenalidomide induces degradation of IKZF1 and IKZF3 Oncoimmunology 2014 3 e941742 10.4161/21624011.2014.941742 25610725 PMC4292522

18. Ito T. Handa H. Molecular mechanisms of thalidomide and its derivatives Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2020 96 189 203 10.2183/pjab.96.016 PMC7298168 32522938

19. Barankiewicz J. Salomon-Perzyński A. Misiewicz-Krzemińska I. Lech-Marańda E. CRL4(CRBN) E3 ligase complex as a therapeutic target in multiple myeloma Cancers 2022 14 4492 10.3390/cancers14184492 36139651 PMC9496858

20. LaPlante G. Zhang W. Targeting the ubiquitin-proteasome system for cancer therapeutics by small-molecule Inhibitors Cancers 2021 13 3079 10.3390/cancers13123079 34203106 PMC8235664

21. Faust T.B. Donovan K.A. Yue H. Chamberlain P.P. Fischer E.S. Small-molecule approaches to targeted protein degradation Annu. Rev. Cancer Biol. 2021 5 181 201 10.1146/annurev-cancerbio-051420-114114

22. Békés M. Langley D.R. Crews C.M. PROTAC targeted protein degraders: The past is prologue Nat. Rev. Drug Discov. 2022 21 181 200 10.1038/s41573-021-00371-6 35042991 PMC8765495

23. Siegel D.S. Schiller G.J. Samaras C. Sebag M. Berdeja J. Ganguly S. Matous J. Song K. Seet C.S. Talamo G. Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment Leukemia 2020 34 3286 3297 10.1038/s41375-020-0813-1 32376855 PMC7685974

24. Dimopoulos M. Weisel K. Moreau P. Anderson L.D. Jr. White D. San-Miguel J. Sonneveld P. Engelhardt M. Jenner M. Corso A. Pomalidomide, bortezomib, and dexamethasone for multiple myeloma previously treated with lenalidomide (OPTIMISMM): Outcomes by prior treatment at first relapse Leukemia 2021 35 1722 1731 10.1038/s41375-020-01021-3 32895455 PMC8179841

25. Alabi S.B. Crews C.M. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs J. Biol. Chem. 2021 296 100647 10.1016/j.jbc.2021.100647 33839157 PMC8131913

26. Jan M. Sperling A.S. Ebert B.L. Cancer therapies based on targeted protein degradation—Lessons learned with lenalidomide Nat. Rev. Clin. Oncol. 2021 18 401 417 10.1038/s41571-021-00479-z 33654306 PMC8903027

27. Matyskiela M.E. Zhang W. Man H.W. Muller G. Khambatta G. Baculi F. Hickman M. LeBrun L. Pagarigan B. Carmel G. A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos J. Med. Chem. 2018 61 535 542 10.1021/acs.jmedchem.6b01921 28425720

28. Lonial S. Popat R. Hulin C. Jagannath S. Oriol A. Richardson P.G. Facon T. Weisel K. Larsen J.T. Minnema M.C. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): A multicentre, multicohort, open-label, phase 1/2 trial Lancet Haematol. 2022 9 e822 e832 10.1016/S2352-3026(22)00290-3 36209764

29. Hagner P.R. Man H.W. Fontanillo C. Wang M. Couto S. Breider M. Bjorklund C. Havens C.G. Lu G. Rychak E. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL Blood 2015 126 779 789 10.1182/blood-2015-02-628669 26002965 PMC4528065

30. Rasco D.W. Papadopoulos K.P. Pourdehnad M. Gandhi A.K. Hagner P.R. Li Y. Wei X. Chopra R. Hege K. DiMartino J. A first-in-human study of novel cereblon modulator avadomide (CC-122) in advanced malignancies Clin. Cancer Res. 2019 25 90 98 10.1158/1078-0432.CCR-18-1203 30201761

31. Hansen J.D. Correa M. Nagy M.A. Alexander M. Plantevin V. Grant V. Whitefield B. Huang D. Kercher T. Harris R. Discovery of CRBN E3 ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myeloma J. Med. Chem. 2020 63 6648 6676 10.1021/acs.jmedchem.9b01928 32130004

32. Wong L. Lamba M. Nunez M.D.J. Bauer D. Richardson P.G. Bahlis N.J. Vangsted A.J. Ramasamy K. Trudel S. Martinez-Lopez J. Dose- and schedule-dependent immunomodulatory effects of the novel Celmod agent CC-92480 in patients with relapsed/refractory multiple myeloma Blood 2020 136 47 48 10.1182/blood-2020-137161

33. Richardson P.G. Vangsted A.J. Ramasamy K. Trudel S. Martinez J. Mateos M.V. Otero P.R. Lonial S. Popat R. Oriol A. First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) J. Clin. Oncol. 2020 38 8500 10.1200/JCO.2020.38.15_suppl.8500

34. Lonial S. Berdeja J.G. Dimopoulos M.A. Jagannath S. Knop S. Quach H. Rodriguez-Otero P. Richardson P.G. Sorrell A. Chen M. EXCALIBER: A phase 3 study comparing iberdomide, daratumumab, and dexamethasone (IberDd) with daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma Clin. Lymphoma Myeloma Leuk. 2021 21 S150 10.1016/S2152-2650(21)02330-2

35. Weisel K. Knop S. Lonial S. Richardson P.G. Popat R. Stadtmauer E.A. Larsen J.T. Oriol A. Jagannath S. Cook G. Iberdomide (IBER) in combination with dexamethasone (DEX) and daratumumab (DARA), bortezomib (BORT), or carfilzomib (CFZ) in patients with relapsed/refractory multiple myeloma (RRMM) Oncol. Res. Treat. 2021 44 86 87

36. Pickart C.M. Eddins M.J. Ubiquitin: Structures, functions, mechanisms Biochim. Biophys. Acta 2004 1695 55 72 10.1016/j.bbamcr.2004.09.019 15571809

37. Imtiaz H. Khan M. Ehsan H. Wahab A. Rafae A. Khan A.Y. Jamil A. Sana M.K. Jamal A. Ali T.J. Efficacy and toxicity profile of carfilzomib-based regimens for treatment of newly diagnosed multiple myeloma: A systematic review Onco Targets Ther. 2021 14 4941 4960 10.2147/OTT.S317570 34629878 PMC8493667

38. Latif A. Kapoor V. Lateef N. Ahsan M.J. Usman R.M. Malik S.U. Ahmad N. Rosko N. Rudoni J. William P. Incidence and management of carfilzomib-induced cardiovascular toxicity; a systematic review and meta-analysis Cardiovasc. Hematol. Disord. Drug Targets 2021 21 30 45 10.2174/1871529X21666210412113017 33845729

39. Das A. Dasgupta S. Gong Y. Shah U.A. Fradley M.G. Cheng R.K. Roy B. Guha A. Cardiotoxicity as an adverse effect of immunomodulatory drugs and proteasome inhibitors in multiple myeloma: A network meta-analysis of randomized clinical trials Hematol. Oncol. 2022 40 233 242 10.1002/hon.2959 34940983 PMC9423942

40. Xie J. Wan N. Liang Z. Zhang T. Jiang J. Ixazomib—The first oral proteasome inhibitor Leuk. Lymphoma 2019 60 610 618 10.1080/10428194.2018.1523398 30614337

41. Richardson P.G. Moreau P. Laubach J.P. Gupta N. Hui A.M. Anderson K.C. San Miguel J.F. Kumar S. The investigational proteasome inhibitor ixazomib for the treatment of multiple myeloma Future Oncol. 2015 11 1153 1168 10.2217/fon.15.9 25832873

42. Das D.S. Ray A. Song Y. Richardson P. Trikha M. Chauhan D. Anderson K.C. Synergistic anti-myeloma activity of the proteasome inhibitor marizomib and the IMiD immunomodulatory drug pomalidomide Br. J. Haematol. 2015 171 798 812 10.1111/bjh.13780 26456076 PMC4715649

43. Spencer A. Harrison S. Zonder J. Badros A. Laubach J. Bergin K. Khot A. Zimmerman T. Chauhan D. Levin N. A phase 1 clinical trial evaluating marizomib, pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107): Final study results Br. J. Haematol. 2018 180 41 51 10.1111/bjh.14987 29076150 PMC6860364

44. Tang W. Li Y. Liang Q. Qu Y. Zhang L. Liu Y. Fang B. Yun Z. Du X. Xi Y. Phase I study of a novel oral proteasome inhibitor TQB3602 in relapsed/refractory multiple myeloma Blood 2022 140 4396 4397 10.1182/blood-2022-168091

45. Tang W. Li Y. Zhong X. Liang Q. Liu Y. Zeng Y. Fang B. Zheng L. Niu T. Phase I study of TQB3602 capsule, an oral proteasome inhibitor, in relapsed refractory multiple myeloma Hemasphere 2022 6 843 844 10.1097/01.HS9.0000846680.89917.3a PMC11259557 39031941

46. Lei H. Wang J. Hu J. Zhu Q. Wu Y. Deubiquitinases in hematological malignancies Biomark. Res. 2021 9 66 10.1186/s40364-021-00320-w 34454635 PMC8401176

47. Chauhan D. Tian Z. Nicholson B. Kumar K.G. Zhou B. Carrasco R. McDermott J.L. Leach C.A. Fulcinniti M. Kodrasov M.P. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance Cancer Cell 2012 22 345 358 10.1016/j.ccr.2012.08.007 22975377 PMC3478134

48. Wang X. Mazurkiewicz M. Hillert E.K. Olofsson M.H. Pierrou S. Hillertz P. Gullbo J. Selvaraju K. Paulus A. Akhtar S. The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells Sci. Rep. 2016 6 26979 10.1038/srep26979 27264969 PMC4893612

49. Rowinsky E.K. Paner A. Berdeja J.G. Paba-Prada C. Venugopal P. Porkka K. Gullbo J. Linder S. Loskog A. Richardson P.G. Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma Investig. New Drugs 2020 38 1448 1453 10.1007/s10637-020-00915-4 32125598 PMC7497669

50. Ying J. Zhang M. Qiu X. Lu Y. Targeting the neddylation pathway in cells as a potential therapeutic approach for diseases Cancer Chemother. Pharmacol. 2018 81 797 808 10.1007/s00280-018-3541-8 29450620

51. Zhou L. Jia L. Targeting protein neddylation for cancer therapy Adv. Exp. Med. Biol. 2020 1217 297 315 10.1007/978-981-15-1025-0_18 31898235

52. Yu Q. Jiang Y. Sun Y. Anticancer drug discovery by targeting cullin neddylation Acta Pharm. Sin. B 2020 10 746 765 10.1016/j.apsb.2019.09.005 32528826 PMC7276695

53. Li L. Wang M. Yu G. Chen P. Li H. Wei D. Zhu J. Xie L. Jia H. Shi J. Overactivated neddylation pathway as a therapeutic target in lung cancer J. Natl. Cancer Inst. 2014 106 dju083 10.1093/jnci/dju083 24853380

54. Xie P. Yang J.P. Cao Y. Peng L.X. Zheng L.S. Sun R. Meng D.F. Wang M.Y. Mei Y. Qiang Y.Y. Promoting tumorigenesis in nasopharyngeal carcinoma, NEDD8 serves as a potential theranostic target Cell Death Dis. 2017 8 e2834 10.1038/cddis.2017.195 28569775 PMC5520881

55. McMillin D.W. Jacobs H.M. Delmore J.E. Buon L. Hunter Z.R. Monrose V. Yu J. Smith P.G. Richardson P.G. Anderson K.C. Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma Mol. Cancer Ther. 2012 11 942 951 10.1158/1535-7163.MCT-11-0563 22246439 PMC3755358

56. Faessel H.M. Mould D.R. Zhou X. Faller D.V. Sedarati F. Venkatakrishnan K. Population pharmacokinetics of pevonedistat alone or in combination with standard of care in patients with solid tumours or haematological malignancies Br. J. Clin. Pharmacol. 2019 85 2568 2579 10.1111/bcp.14078 31355467 PMC6848912

57. Yoshimura C. Muraoka H. Ochiiwa H. Tsuji S. Hashimoto A. Kazuno H. Nakagawa F. Komiya Y. Suzuki S. Takenaka T. TAS4464, a highly potent and selective inhibitor of NEDD8-activating enzyme, suppresses neddylation and shows antitumor activity in diverse cancer models Mol. Cancer Ther. 2019 18 1205 1216 10.1158/1535-7163.MCT-18-0644 31092565

58. Shah J.J. Jakubowiak A.J. O’Connor O.A. Orlowski R.Z. Harvey R.D. Smith M.R. Lebovic D. Diefenbach C. Kelly K. Hua Z. Phase I study of the novel investigational NEDD8-activating enzyme inhibitor pevonedistat (MLN4924) in patients with relapsed/refractory multiple myeloma or lymphoma Clin. Cancer Res. 2016 22 34 43 10.1158/1078-0432.CCR-15-1237 26561559 PMC5694347

59. Taylor B.C. Young N.L. Combinations of histone post-translational modifications Biochem. J. 2021 478 511 532 10.1042/BCJ20200170 33567070

60. Martire S. Banaszynski L.A. The roles of histone variants in fine-tuning chromatin organization and function Nat. Rev. Mol. Cell Biol. 2020 21 522 541 10.1038/s41580-020-0262-8 32665685 PMC8245300

61. Ilango S. Paital B. Jayachandran P. Padma P.R. Nirmaladevi R. Epigenetic alterations in cancer Front. Biosci. 2020 25 1058 1109 10.2741/4847 32114424

62. Shvedunova M. Akhtar A. Modulation of cellular processes by histone and non-histone protein acetylation Nat. Rev. Mol. Cell Biol. 2022 23 329 349 10.1038/s41580-021-00441-y 35042977

63. Choudhary C. Kumar C. Gnad F. Nielsen M.L. Rehman M. Walther T.C. Olsen J.V. Mann M. Lysine acetylation targets protein complexes and co-regulates major cellular functions Science 2009 325 834 840 10.1126/science.1175371 19608861

64. Milazzo G. Mercatelli D. Di Muzio G. Triboli L. De Rosa P. Perini G. Giorgi F.M. Histone deacetylases (HDACs): Evolution, specificity, role in transcriptional complexes, and pharmacological actionability Genes 2020 11 556 10.3390/genes11050556 32429325 PMC7288346

65. Caprio C. Sacco A. Giustini V. Roccaro A.M. Epigenetic aberrations in multiple myeloma Cancers 2020 12 2996 10.3390/cancers12102996 33076518 PMC7602661

66. Mithraprabhu S. Kalff A. Chow A. Khong T. Spencer A. Dysregulated class I histone deacetylases are indicators of poor prognosis in multiple myeloma Epigenetics 2014 9 1511 1520 10.4161/15592294.2014.983367 25482492 PMC4622977

67. Weichert W. HDAC expression and clinical prognosis in human malignancies Cancer Lett. 2009 280 168 176 10.1016/j.canlet.2008.10.047 19103471

68. Ruzic D. Djoković N. Srdić-Rajić T. Echeverria C. Nikolic K. Santibanez J.F. Targeting histone deacetylases: Opportunities for cancer treatment and chemoprevention Pharmaceutics 2022 14 209 10.3390/pharmaceutics14010209 35057104 PMC8778744

69. Dimopoulos M. Siegel D.S. Lonial S. Qi J. Hajek R. Facon T. Rosinol L. Williams C. Blacklock H. Goldschmidt H. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): A multicentre, randomised, double-blind study Lancet Oncol. 2013 14 1129 1140 10.1016/S1470-2045(13)70398-X 24055414

70. Richardson P.G. Hungria V.T. Yoon S.S. Beksac M. Dimopoulos M.A. Elghandour A. Jedrzejczak W.W. Guenther A. Nakorn T.N. Siritanaratkul N. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by prior treatment Blood 2016 127 713 721 10.1182/blood-2015-09-665018 26631116 PMC4760132

71. Huang H.H. Hou J. Zhang Y.M. Zhou Y.B. Jia L. Nan F.J. Phase 1 study of bisthianostat, an orally efficacious pan-HDAC inhibitor: Part results of safety, pharmacokinetics and efficacy in patients with relapsed or refractory multiple myeloma Blood 2019 134 5591 10.1182/blood-2019-129683

72. Zhou Y.B. Zhang Y.M. Huang H.H. Shen L.J. Han X.F. Hu X.B. Yu S.D. Gao A.H. Sheng L. Su M.B. Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma Acta Pharmacol. Sin. 2021 43 1091 1099 10.1038/s41401-021-00728-y 34341512 PMC8976035

73. Vogl D.T. Raje N.S. Jagannath S. Richardson P.G. Hari P. Orlowski R.Z. Supko J.G. Tamang D. Yang M. Jones S.S. Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma Clin. Cancer Res. 2017 23 3307 3315 10.1158/1078-0432.CCR-16-2526 28053023 PMC5496796

74. Yee A.J. Bensinger W.I. Supko J.G. Voorhees P.M. Berdeja J.G. Richardson P.G. Libby E.N. Wallace E.E. Birrer N.E. Burke J.N. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A multicentre phase 1b trial Lancet Oncol. 2016 17 1569 1578 10.1016/S1470-2045(16)30375-8 27646843

75. Yao W. Yan L. Shang J. Jin S. Shi X. Yan S. Wu D. Fu C. Phase 2 Suzhou MM02 study: Chidamide with VRD versus VRD in newly diagnosed high risk transplant eligible multiple myeloma patients Blood 2021 138 4765 10.1182/blood-2021-152390

76. Sborov D.W. Benson D.M. Williams N. Huang Y. Bowers M.A. Humphries K. Efebera Y. Devine S. Hofmeister C.C. Lenalidomide and vorinostat maintenance after autologous transplant in multiple myeloma Br. J. Haematol. 2015 171 74 83 10.1111/bjh.13527 26058589 PMC4600596

77. Siegel D.S. Dimopoulos M. Jagannath S. Goldschmidt H. Durrant S. Kaufman J.L. Leleu X. Nagler A. Offner F. Graef T. VANTAGE 095: An international, multicenter, open-label study of vorinostat (MK-0683) in combination with bortezomib in patients with relapsed and refractory multiple myeloma Clin. Lymphoma Myeloma Leuk. 2016 16 329 334.e1 10.1016/j.clml.2016.02.042 27025160

78. Brown S. Pawlyn C. Tillotson A.L. Sherratt D. Flanagan L. Low E. Morgan G.J. Williams C. Kaiser M. Davies F.E. Bortezomib, vorinostat, and dexamethasone combination therapy in relapsed myeloma: Results of the phase 2 MUK four trial Clin. Lymphoma Myeloma Leuk. 2021 21 154 161.e3 10.1016/j.clml.2020.11.019 33478922

79. Kaufman J.L. Mina R. Shah J.J. Laubach J.P. Nooka A.K. Lewis C. Gleason C. Sharp C. Harvey R.D. Heffner L.T. Phase 1 trial evaluating vorinostat plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma Clin. Lymphoma Myeloma Leuk. 2020 20 797 803 10.1016/j.clml.2020.07.013 32819881

80. Vesole D.H. Bilotti E. Richter J.R. McNeill A. McBride L. Raucci L. Anand P. Bednarz U. Ivanovski K. Smith J. Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma Br. J. Haematol. 2015 171 52 59 10.1111/bjh.13517 26018491

81. Waldschmidt J.M. Keller A. Ihorst G. Grishina O. Muller S. Wider D. Frey A.V. King K. Simon R. May A. Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: Vorinostat in elderly, relapsed and unfit multiple myeloma) Haematologica 2018 103 e473 e479 10.3324/haematol.2018.189969 29674494 PMC6165805

82. Niesvizky R. Richardson P.G. Gabrail N.Y. Madan S. Yee A.J. Quayle S.N. Almeciga-Pinto I. Jones S.S. Houston L. Hayes D. ACY-241, a novel, HDAC6 selective inhibitor: Synergy with immunomodulatory (IMiD (R)) drugs in multiple myeloma (MM) cells and early clinical results (ACE-MM-200 study) Blood 2015 126 3 10.1182/blood.V126.23.3040.3040

83. Niesvizky R. Richardson P.G. Yee A.J. Nooka A.K. Raab M.S. Shain K.H. Gabrail N.Y. Matous J. Agarwal A.B. Hoffman J. Selective HDAC6 inhibitor ACY-241, an oral tablet, combined with pomalidomide and dexamethasone: Safety and efficacy of escalation and expansion cohorts in patients with relapsed or relapsed-and-refractory multiple myeloma (ACE-MM-200 study) Blood 2016 128 7 10.1182/blood.V128.22.3307.3307

84. North B.J. Almeciga-Pinto I. Tamang D. Yang M. Jones S.S. Quayle S.N. Enhancement of pomalidomide anti-tumor response with ACY-241, a selective HDAC6 inhibitor PLoS ONE 2017 12 16 10.1371/journal.pone.0173507 28264055 PMC5338861

85. Shang J.J. Yao W.Q. Yan L.Z. Shi X.L. Wang R.J. Yan S. Liu Y. Wu D.P. Cheng F.C. Initial safety and efficacy of dose-escalating HDACs inhibitor chidamide with VRD (Chi-VRD) treatment for newly-diagnosed high-risk transplant eligible multiple myeloma patients Blood 2019 134 1855 10.1182/blood-2019-129434

86. Filippakopoulos P. Knapp S. The bromodomain interaction module FEBS Lett. 2012 586 2692 2704 10.1016/j.febslet.2012.04.045 22710155

87. Gokani S. Bhatt L.K. Bromodomains: A novel target for the anticancer therapy Eur. J. Pharmacol. 2021 911 174523 10.1016/j.ejphar.2021.174523 34563497

88. Ferri E. Petosa C. McKenna C.E. Bromodomains: Structure, function and pharmacology of inhibition Biochem. Pharmacol. 2016 106 1 18 10.1016/j.bcp.2015.12.005 26707800

89. Llombart V. Mansour M.R. Therapeutic targeting of “undruggable” MYC eBioMedicine 2022 75 103756 10.1016/j.ebiom.2021.103756 34942444 PMC8713111

90. Delmore J.E. Issa G.C. Lemieux M.E. Rahl P.B. Shi J.W. Jacobs H.M. Kastritis E. Gilpatrick T. Paranal R.M. Qi J. BET bromodomain inhibition as a therapeutic strategy to target c-Myc Cell 2011 146 903 916 10.1016/j.cell.2011.08.017 PMC3187920 21889194

91. Jung M. Gelato K.A. Fernandez-Montalvan A. Siegel S. Haendler B. Targeting BET bromodomains for cancer treatment Epigenomics 2015 7 487 501 10.2217/epi.14.91 26077433

92. Martin M.P. Olesen S.H. Georg G.I. Schonbrunn E. Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains ACS Chem. Biol. 2013 8 2360 2365 10.1021/cb4003283 24007471 PMC3846258

93. Chng W.J. Huang G.F. Chung T.H. Ng S.B. Gonzalez-Paz N. Troska-Price T. Mulligan G. Chesi M. Bergsagel P.L. Fonseca R. Clinical and biological implications of MYC activation: A common difference between MGUS and newly diagnosed multiple myeloma Leukemia 2011 25 1026 1035 10.1038/leu.2011.53 21468039 PMC3432644

94. Aird F. Kandela I. Mantis C. Replication study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc eLife 2017 6 e21253 10.7554/eLife.21253 28100400 PMC5245966

95. Todaro M. Boi M. Vurchio V. Ercole E. Machiorlatti R. Messana K. Landra I. Urigu S. Aliberti S. Riveiro E. OTX015, a novel BET inhibitor, is a promising anticancer agent for multiple myeloma Cancer Res. 2014 74 5531 10.1158/1538-7445.AM2014-5531

96. Amorim S. Stathis A. Gleeson M. Iyengar S. Magarotto V. Leleu X. Morschhauser F. Karlin L. Broussais F. Rezai K. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: A dose-escalation, open-label, pharmacokinetic, phase 1 study Lancet Haematol. 2016 3 e196 e204 10.1016/S2352-3026(16)00021-1 27063978

97. Albrecht B.K. Gehling V.S. Hewitt M.C. Vaswani R.G. Cote A. Leblanc Y. Nasveschuk C.G. Bellon S. Bergeron L. Campbell R. Identification of a benzoisoxazoloazepine inhibitor (CPI-0610) of the bromodomain and extra-terminal (BET) family as a candidate for human clinical trials J. Med. Chem. 2016 59 1330 1339 10.1021/acs.jmedchem.5b01882 26815195

98. Ramasamy K. Nooka A. Quach H. Htut M. Popat R. Liedtke M. Tuchman S.A. Laubach J.P. Gasparetto C. Chanan-Khan A.A. Open label, multicenter, dose-escalation/ expansion phase Ib study to evaluate safety and activity of BET Inhibitor RO6870810 (RO), given as monotherapy to patients (pts) with advanced multiple myeloma Blood 2020 136 12 10.1182/blood-2020-136392

99. Siu K.T. Eda H. Santo L. Ramachandran J. Koulnis M. Mertz J. Sims R.J. Cooper M. Raje N.S. Effect of the BET inhibitor, CPI-0610, alone and in combination with lenalidomide in multiple myeloma Blood 2015 126 4255 10.1182/blood.V126.23.4255.4255

100. Klener P. Sovilj D. Renesova N. Andera L. BH3 mimetics in hematologic malignancies Int. J. Mol. Sci. 2021 22 10157 10.3390/ijms221810157 34576319 PMC8466478

101. Yap J.L. Chen L. Lanning M.E. Fletcher S. Expanding the cancer arsenal with targeted therapies: Disarmament of the anti-apoptotic Bcl-2 proteins by small-molecules J. Med. Chem. 2016 60 821 838 10.1021/acs.jmedchem.5b01888 27749061

102. Krishna S. Kumar S.B. Murthy T.P.K. Murahari M. Structure-based design approach of potential BCL-2 inhibitors for cancer chemotherapy Comput. Biol. Med. 2021 134 104455 10.1016/j.compbiomed.2021.104455 33962088

103. Ashkenazi A. Fairbrother W.J. Leverson J.D. Souers A.J. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors Nat. Rev. Drug Discov. 2017 16 273 284 10.1038/nrd.2016.253 28209992

104. Kumar S. Harrison S.J. Cavo M. de La Rubia J. Popat R. Gasparetto C. Hungria V. Salwender H. Suzuki K. Kim I. Updated results from BELLINI, a phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma J. Clin. Oncol. 2020 38 8509 10.1200/JCO.2020.38.15_suppl.8509 33129376

105. Mateos M.V. Moreau P. Dimopoulos M.A. Hong W.J. Cooper S. Yu Y. Jalaluddin M. Ross J.A. Karve S. Coppola S. A phase III, randomized, multicenter, open-label study of venetoclax or pomalidomide in combination with dexamethasone in patients with t(11;14)-positive relapsed/refractory multiple myeloma J. Clin. Oncol. 2020 38 TPS8554 10.1200/JCO.2020.38.15_suppl.TPS8554

106. Fu C.C. Chen Z. Li W.S. Men L.C. Wu D.P. Yang D.J. Zhai Y.F. Trial in progress: Phase 1b/2 open-label study of lisaftoclax (APG-2575) monotherapy or in combination with lenalidomide/dexamethasone in patients with relapsed or refractory multiple myeloma (R/R MM) Blood 2021 138 4764 10.1182/blood-2021-151631

107. Hu N. Guo Y.H. Xue H. Liu Y. Guo Y. Wang F. Song X.M. Guo Y. Chen S.S. Xu H.P. Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in haematological tumor models Cancer Res. 2020 80 3077 10.1158/1538-7445.AM2020-3077

108. Quach H. Rajagopal R. Spencer A. Low M. Kazandjian D. Crescenzo R. Du C. Patel S. Mundra V. Cheng H. Preliminary safety of a Bcl-2 Inhibitor, Bgb-11417, in patients with relapsed/refractory multiple myeloma harboring t(11,14): A non-randomized, open-label, phase 1b/2 study Blood 2022 140 7269 7271 10.1182/blood-2022-169666

109. Lu X. Liang H. Orvig C. Chen Z.F. Peptide and small molecule inhibitors targeting myeloid cell leukemia 1 (Mcl-1) as novel antitumor agents Curr. Mol. Med. 2021 21 426 439 10.2174/1566524020666200929121016 32990536

110. Spencer A. Rosenberg A.S. Jakubowiak A. Raje N. Chatterjee M. Trudel S. Bahlis N.J. Siegel D.S. Wilop S. Harrison S.J. A phase 1, first-in-human study of AMG 176, a selective MCL-1 Inhibitor, in patients with relapsed or refractory multiple myeloma Clin. Lymphoma Myeloma Leuk. 2019 19 E53 E54 10.1016/j.clml.2019.09.081

111. Halilovic E. Chanrion M. Mistry P. Wartmann M. Qiu S.M. Sanghavi S. Chen Y. Lysiak G. Maragno A.L. Pfaar U. MIK665/S64315, a novel Mcl-1 inhibitor, in combination with Bcl-2 inhibitors exhibits strong synergistic antitumor activity in a range of hematologic malignancies Cancer Res. 2019 79 4477 10.1158/1538-7445.AM2019-4477

112. Bhagwat N. Grego A. Gowen-MacDonald W. Wang M. Cowart M. Wu X.W. Zhuo J.C. Combs A. Ruggeri B. Scherle P. Preclinical characterization of PRT1419, a potent, selective and orally available inhibitor of MCL1 Cancer Res. 2021 81 983 10.1158/1538-7445.AM2021-983

113. Matulis S.M. Gupta V.A. Brown I. Keats J.J. Secrist P. Cidado J. Tron A.E. Neri P. Bahlis N. Kaufman J.L. Preclinical activity of novel MCL1 inhibitor AZD5991 in multiple myeloma Blood 2018 132 952 10.1182/blood-2018-99-113504

114. Zhang L. Sun S. Wang Y. Mo Y. Xiong F. Zhang S. Zeng Z. Xiong W. Li G. Chen H. Gossypol induces apoptosis of multiple myeloma cells through the JUN-JNK pathway Am. J. Cancer Res. 2020 10 870 883 32266096 PMC7136925

115. Ailawadhi S. Alegria V.R. Ahmed S. Laplant B. Manna A. Parrondo R. Roy V. Sher T. Edwards B. Lanier S. Phase I Study of a novel Bcl-2 inhibitor, AT-101 in combination with lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma (RRMM) Blood 2019 134 3137 10.1182/blood-2019-128610

116. Parrondo R.D. Paulus A. Ailawadhi S. Updates in the Use of BCL-2-family small molecule inhibitors for the treatment of relapsed/refractory multiple myeloma Cancers 2022 14 3330 10.3390/cancers14143330 35884390 PMC9317574

117. Bahlis N.J. Baz R. Harrison S.J. Quach H. Ho S.J. Vangsted A.J. Plesner T. Moreau P. Gibbs S.D. Coppola S. Phase I study of venetoclax plus daratumumab and dexamethasone, with or without bortezomib, in patients with relapsed or refractory multiple myeloma with and without t(11;14) J. Clin. Oncol. 2021 39 3602 3612 10.1200/JCO.21.00443 34388020 PMC8577687

118. Kaufman J.L. Quach H. Baz R. Vangsted A.J. Ho S.J. Harrison S.J. Plesner T. Moreau P. Gibbs S.D. Medvedova E. Safety and preliminary efficacy from the expansion cohort of a phase 1/2 study of venetoclax plus daratumumab and dexamethasone vs daratumumab plus bortezomib and dexamethasone in patients with t(11;14) relapsed/refractory multiple myeloma Blood 2021 138 (Suppl. S1) 817 10.1182/blood-2021-146043

119. Costa L.J. Davies F.E. Monohan G.P. Kovacsovics T.J. Burwick N. Jakubowiak A.J. Kaufman J.L. Hong W.J. Dail M. Salem A.H. Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma Blood Adv. 2021 5 3748 3759 10.1182/bloodadvances.2020004146 34470049 PMC8679663

120. Kumar S. Kaufman J.L. Gasparetto C. Mikhael J. Vij R. Pegourie B. Benboubker L. Facon T. Amiot M. Moreau P. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma Blood 2017 130 2401 2409 10.1182/blood-2017-06-788786 29018077

121. Kaufman J.L. Gasparetto C. Schjesvold F.H. Moreau P. Touzeau C. Facon T. Boise L.H. Jiang Y. Yang X. Dunbar F. Targeting BCL-2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma Am. J. Hematol. 2021 96 418 427 10.1002/ajh.26083 33368455 PMC7986778

122. Kumar S. Harrison S.J. Cavo M. de la Rubia J. Popat R. Gasparetto C.J. Hungria V. Salwender H. Suzuki K. Kim I. Final overall survival results from BELLINI, a phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma Blood 2021 138 84 10.1182/blood-2021-145757 33129376

123. Shahin R. Aljamal S. Kinesin spindle protein inhibitors in cancer: From high throughput screening to novel therapeutic strategies Future Sci. OA 2022 8 Fso778 10.2144/fsoa-2021-0116 35251692 PMC8890118

124. Humphries M.J. Anderson D. Williams L. Rieger R. ARRY-520 combined with pomalidomide displays enhanced anti-tumor activity in preclinical models of multiple myeloma Blood 2013 122 3167 10.1182/blood.V122.21.3167.3167

125. Woessner R. Tunquist B. Lemieux C. Chlipala E. Jackinsky S. Dewolf W. Jr. Voegtli W. Cox A. Rana S. Lee P. ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models Anticancer Res. 2009 29 4373 4380 20032381

126. Shah J.J. Kaufman J.L. Zonder J.A. Cohen A.D. Bensinger W.I. Hilder B.W. Rush S.A. Walker D.H. Tunquist B.J. Litwiler K.S. A phase 1 and 2 study of filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory multiple myeloma Cancer 2017 123 4617 4630 10.1002/cncr.30892 28817190 PMC5856158

127. Chari A. Htut M. Zonder J.A. Fay J.W. Jakubowiak A.J. Levy J.B. Lau K. Burt S.M. Tunquist B.J. Hilder B.W. A phase 1 dose-escalation study of filanesib plus bortezomib and dexamethasone in patients with recurrent/refractory multiple myeloma Cancer 2016 122 3327 3335 10.1002/cncr.30174 27433944 PMC6857452

128. Pan D. Kaufman J.L. Htut M. Agrawal M. Mazumder A. Cornell R.F. Zonder J.A. Fay J.W. Modiano M.R. Moshier E.L. Filanesib plus bortezomib and dexamethasone in relapsed/refractory t(11;14) and 1q21 gain multiple myeloma Cancer Med. 2022 11 358 370 10.1002/cam4.4451 34921527 PMC8729045

129. Hanamura I. Gain/amplification of chromosome arm 1q21 in multiple myeloma Cancers 2021 13 256 10.3390/cancers13020256 33445467 PMC7827173

130. Schmidt T.M. Barwick B.G. Joseph N. Heffner L.T. Hofmeister C.C. Bernal L. Dhodapkar M.V. Gupta V.A. Jaye D.L. Wu J. Gain of chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone Blood Cancer J. 2019 9 94 10.1038/s41408-019-0254-0 31767829 PMC6877577

131. Mohan M. Weinhold N. Schinke C. Thanedrarajan S. Rasche L. Sawyer J.R. Tian E. van Rhee F. Zangari M. Daratumumab in high-risk relapsed/refractory multiple myeloma patients: Adverse effect of chromosome 1q21 gain/amplification and GEP70 status on outcome Br. J. Haematol. 2020 189 67 71 10.1111/bjh.16292 31820442

132. Lee H.C. Shah J.J. Feng L. Manasanch E.E. Lu R. Morphey A. Crumpton B. Patel K.K. Wang M.L. Alexanian R. A phase 1 study of filanesib, carfilzomib, and dexamethasone in patients with relapsed and/or refractory multiple myeloma Blood Cancer J. 2019 9 80 10.1038/s41408-019-0240-6 31575851 PMC6773683

133. Ocio E.M. Motllo C. Rodriguez-Otero P. Martinez-Lopez J. Cejalvo M.J. Martin-Sanchez J. Blade J. Garcia-Malo M.D. Dourdil M.V. Garcia-Mateo A. Filanesib in combination with pomalidomide and dexamethasone in refractory MM patients: Safety and efficacy, and association with alpha 1-acid glycoprotein (AAG) levels. Phase Ib/II Pomdefil clinical trial conducted by the Spanish MM group Br. J. Haematol. 2021 192 522 530 10.1111/bjh.16788 32501528

134. Alexandrakis M.G. Passam F.H. Ganotakis E.S. Sfiridaki K. Xilouri I. Perisinakis K. Kyriakou D.S. The clinical and prognostic significance of erythrocyte sedimentation rate (ESR), serum interleukin-6 (IL-6) and acute phase protein levels in multiple myeloma Clin. Lab. Haematol. 2003 25 41 46 10.1046/j.1365-2257.2003.00492.x 12542441

135. Tunquist B. Brown K. Hingorani G. Aitchison R. Regensburger J. Lonial S. Kaufman J. Zonder J. Cohen A. Bensinger W. Alpha 1-acid glycoprotein (AAG) is a potential patient selection biomarker for improved clinical activity of ARRY-520 in relapsed and refractory multiple myeloma (MM) Haematologica 2013 98 328 329

136. Algarin E.M. Hernandez-Garcia S. Garayoa M. Ocio E.M. Filanesib for the treatment of multiple myeloma Expert Opin. Investig. Drugs 2020 29 5 14 10.1080/13543784.2020.1703179 31815551

137. Zonder J.A. Usiinani S. Scott E.C. Harneister C.C. Lendvai N. Berdeja J.C. Anderson L.D. Hari P. Singhal S. Orloff G. Phase 2 study of carfilzomib (CFZ) with or without filanesib (FIL) in patients with advanced multiple myeloma (MM) Blood 2015 126 728 10.1182/blood.V126.23.728.728

138. Lonial S. Delforge M. Einsele H. Moreau P. Kaiser M. Dimopoulos M.A. Oriol A. Gyger M. Hilder B. Ptaszynski A.M. The AfFIRM study: A multicenter phase 2 study of single-agent filanesib (ARRY-520) in patients with advanced multiple myeloma J. Clin. Oncol. 2015 33 TPS8613 10.1200/jco.2015.33.15_suppl.tps8613

139. Schwartz T.U. Solving the nuclear pore puzzle Science 2022 376 1158 1159 10.1126/science.abq4792 35679398

140. Raices M. D’Angelo M.A. Structure, maintenance, and regulation of nuclear pore complexes: The gatekeepers of the eukaryotic genome Cold Spring Harb. Perspect. Biol. 2022 14 a040691 10.1101/cshperspect.a040691 34312247 PMC8789946

141. Azmi A.S. Uddin M.H. Mohammad R.M. The nuclear export protein XPO1—From biology to targeted therapy Nat. Rev. Clin. Oncol. 2021 18 152 169 10.1038/s41571-020-00442-4 33173198

142. Li S. Fu J. Lu C. Mapara M.Y. Raza S. Hengst U. Lentzsch S. Elevated translation initiation factor eIF4E Is an attractive therapeutic target in multiple myeloma Mol. Cancer Ther. 2016 15 711 719 10.1158/1535-7163.MCT-15-0798 26939700

143. Tai Y.T. Landesman Y. Acharya C. Calle Y. Zhong M.Y. Cea M. Tannenbaum D. Cagnetta A. Reagan M. Munshi A.A. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: Molecular mechanisms and therapeutic implications Leukemia 2014 28 155 165 10.1038/leu.2013.115 23588715 PMC3883926

144. Schmidt J. Braggio E. Kortuem K.M. Egan J.B. Zhu Y.X. Xin C.S. Tiedemann R.E. Palmer S.E. Garbitt V.M. McCauley D. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276 Leukemia 2013 27 2357 2365 10.1038/leu.2013.172 23752175 PMC3922416

145. Kudo N. Matsumori N. Taoka H. Fujiwara D. Schreiner E.P. Wolff B. Yoshida M. Horinouchi S. Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region Proc. Natl. Acad. Sci. USA 1999 96 9112 9117 10.1073/pnas.96.16.9112 10430904 PMC17741

146. Syed Y.Y. Selinexor: First global approval Drugs 2019 79 1485 1494 10.1007/s40265-019-01188-9 31429063

147. Chari A. Vogl D.T. Gavriatopoulou M. Nooka A.K. Yee A.J. Huff C.A. Moreau P. Dingli D. Cole C. Lonial S. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma N. Engl. J. Med. 2019 381 727 738 10.1056/NEJMoa1903455 31433920

148. Restrepo P. Bhalla S. Ghodke-Puranik Y. Aleman A. Leshchenko V. Melnekoff D.T. Agte S. Jiang J. Madduri D. Richter J. A three-gene signature predicts response to selinexor in multiple myeloma JCO Precis. Oncol. 2022 6 e2200147 10.1200/PO.22.00147 35704796 PMC10530420

149. Mateos M.V. Gavriatopoulou M. Facon T. Auner H.W. Leleu X. Hájek R. Dimopoulos M.A. Delimpasi S. Simonova M. Špička I. Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma J. Hematol. Oncol. 2021 14 59 10.1186/s13045-021-01071-9 33849608 PMC8045319

150. Grosicki S. Simonova M. Spicka I. Pour L. Kriachok I. Gavriatopoulou M. Pylypenko H. Auner H.W. Leleu X. Doronin V. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): A randomised, open-label, phase 3 trial Lancet 2020 396 1563 1573 10.1016/S0140-6736(20)32292-3 33189178

151. Cornell R.F. Baz R. Richter J.R. Rossi A. Vogl D.T. Chen C. Shustik C. Alvarez M.J. Shen Y. Unger T.J. A phase 1 clinical trial of oral eltanexor in patients with relapsed or refractory multiple myeloma Am. J. Hematol. 2022 97 E54 E58 10.1002/ajh.26420 34817872

152. Turner J.G. Dawson J.L. Grant S. Shain K.H. Dalton W.S. Dai Y. Meads M. Baz R. Kauffman M. Shacham S. Treatment of acquired drug resistance in multiple myeloma by combination therapy with XPO1 and topoisomerase II inhibitors J. Hematol. Oncol. 2016 9 73 10.1186/s13045-016-0304-z 27557643 PMC4997728

153. Tremblay G. Daniele P. Breeze J. Li L. Shah J. Shacham S. Kauffman M. Engelhardt M. Chari A. Nooka A. Quality of life analyses in patients with multiple myeloma: Results from the selinexor (KPT-330) treatment of refractory myeloma (STORM) phase 2b study BMC Cancer 2021 21 993 10.1186/s12885-021-08453-9 34488662 PMC8419947

154. Chari A. Florendo E. Mancia I.S. Cho H. Madduri D. Parekh S. Richter J. Dhadwal A. Thomas J. Jiang G. Optimal supportive care with selinexor improves outcomes in patients with relapsed/refractory multiple myeloma Clin. Lymphoma Myeloma Leuk. 2021 21 e975 e984 10.1016/j.clml.2021.07.014 34404623

155. Gasparetto C. Lentzsch S. Schiller G.J. Callander N.S. Tuchman S. Bahlis N.J. White D. Chen C. Baljevic M. Sutherland H.J. Selinexor, daratumumab, and dexamethasone in patients with relapsed/refractory multiple myeloma (MM) J. Clin. Oncol. 2020 38 8510 10.1200/JCO.2020.38.15_suppl.8510 PMC9176052 35846104

156. Gasparetto C. Schiller G.J. Tuchman S. Callander N.S. Baljevic M. Lentzsch S. Rossi A.C. Kotb R. White D. Bahlis N.J. Once weekly selinexor, carfilzomib, and dexamethasone (SKd) in carfilzomib nonrefractory multiple myeloma (MM) patients J. Clin. Oncol. 2021 39 8038 10.1200/JCO.2021.39.15_suppl.8038

157. Turner J.G. Cui Y. Bauer A.A. Dawson J.L. Gomez J.A. Kim J. Cubitt C.L. Nishihori T. Dalton W.S. Sullivan D.M. Melphalan and exportin 1 inhibitors exert synergistic anti-tumor effects in preclinical models of human multiple myeloma Cancer Res. 2020 80 5344 5354 10.1158/0008-5472.CAN-19-0677 33023948 PMC7718436

158. Jakubowiak A.J. Jasielec J.K. Rosenbaum C.A. Cole C.E. Chari A. Mikhael J. Nam J. McIver A. Severson E. Stephens L.A. Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma Br. J. Haematol. 2019 86 549 560 10.1111/bjh.15969 PMC6772147 31124580

159. Delimpasi S. Mateos M.V. Auner H.W. Gavriatopoulou M. Dimopoulos M.A. Quach H. Pylypenko H. Hájek R. Leleu X. Dolai T.K. Efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in comparison with standard twice-weekly bortezomib and dexamethasone in previously treated multiple myeloma with renal impairment: Subgroup analysis from the BOSTON study Am. J. Hematol. 2021 97 E83 E86 10.1002/ajh.26434 34882831

160. Auner H.W. Gavriatopoulou M. Delimpasi S. Simonova M. Spicka I. Pour L. Dimopoulos M.A. Kriachok I. Pylypenko H. Leleu X. Effect of age and frailty on the efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma Am. J. Hematol. 2021 96 708 718 10.1002/ajh.26172 33755235

161. White D. Chen C. Baljevic M. Tuchman S. Bahlis N.J. Schiller G.J. Lipe B. Kotb R. Sutherland H.J. Madan S. Oral selinexor, pomalidomide, and dexamethasone (XPd) at recommended phase 2 dose in relapsed refractory multiple myeloma (MM) J. Clin. Oncol. 2021 39 8018 10.1200/JCO.2021.39.15_suppl.8018

162. Gasparetto C. Lipe B. Tuchman S. Callander N.S. Lentzsch S. Baljevic M. Rossi A.C. Bahlis N.J. White D. Chen C. Once weekly selinexor, carfilzomib, and dexamethasone (SKd) in patients with relapsed/refractory multiple myeloma (MM) J. Clin. Oncol. 2020 38 (Suppl. S15) 8530 10.1200/JCO.2020.38.15_suppl.8530

163. Rodriguez-Otero P. De La Calle V.G. Sureda A. De Arriba F. Segura M.R. Ribas P. Gonzalez A.P. Gonzalez-Montes Y. Oriol A. Martinez-Lopez J. Selinexor in combination with daratumumab-bortezomib and dexamethasone for the treatment of relapse or refractory multiple myeloma: Initial results of the phase 2, open-label, multicenter GEM-Selibordara study Blood 2021 138 1677 10.1182/blood-2021-147725

164. Sun C. Zhao F. Li J. Zhang C. Li W. Cheng H. Cai H. Chen B. Guo J. Mei J. Preliminary results from the launch study-a multicenter, open-label study of selinexor, dexamethasone and chemotherapy drugs in relapsed/refractory multiple myeloma Blood 2022 140 12613 10.1182/blood-2022-169053

165. Qiu L. Xia Z. Fu C. Chen W. Chang C. Fang B. An G. Wei Y. Cai Z. Gao S. Selinexor plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma previously treated with an immunomodulatory agent and a proteasome inhibitor (MARCH): A phase II, single-arm study BMC Med. 2022 20 108 10.1186/s12916-022-02305-4 35379237 PMC8981703

166. Hafner A. Bulyk M.L. Jambhekar A. Lahav G. The multiple mechanisms that regulate p53 activity and cell fate Nat. Rev. Mol. Cell Biol. 2019 20 199 210 10.1038/s41580-019-0110-x 30824861

167. Baugh E.H. Ke H. Levine A.J. Bonneau R.A. Chan C.S. Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ. 2018 25 154 160 10.1038/cdd.2017.180 29099487 PMC5729536

168. Ho T. Tan B.X. Lane D. How the other half lives: What p53 does when it is not being a transcription factor Int. J. Mol. Sci. 2019 21 13 10.3390/ijms21010013 31861395 PMC6982169

169. Weinhold N. Ashby C. Rasche L. Chavan S.S. Stein C. Stephens O.W. Tytarenko R. Bauer M.A. Meissner T. Deshpande S. Clonal selection and double hit events involving tumor suppressor genes underlie relapse from chemotherapy: Myeloma as a model Blood 2016 128 1735 1744 10.1182/blood-2016-06-723007 27516441 PMC5043128

170. Melvin A.T. Dumberger L.D. Woss G.S. Waters M.L. Allbritton N.L. Identification of a p53-based portable degron based on the MDM2-p53 binding region Analyst 2016 141 570 578 10.1039/C5AN01429H 26456660 PMC6042837

171. Raj N. Attardi L.D. The transactivation domains of the p53 protein Cold Spring Harb. Perspect. Med. 2017 7 a026047 10.1101/cshperspect.a026047 27864306 PMC5204331

172. Herrero A.B. Rojas E.A. Misiewicz-Krzeminska I. Krzeminski P. Gutierrez N.C. Molecular mechanisms of p53 deregulation in cancer: An overview in multiple myeloma Int. J. Mol. Sci. 2016 17 2003 10.3390/ijms17122003 27916892 PMC5187803

173. Ding Q. Zhang Z. Liu J.J. Jiang N. Zhang J. Ross T.M. Chu X.J. Bartkovitz D. Podlaski F. Janson C. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development J. Med. Chem. 2013 56 5979 5983 10.1021/jm400487c 23808545

174. Price S. Al-Bahou A. Navtemadlin Drugs Future 2022 47 247 259 10.1358/dof.2022.47.4.3381587

175. Gluck W.L. Gounder M.M. Frank R. Eskens F. Blay J.Y. Cassier P.A. Soria J.C. Chawla S. de Weger V. Wagner A.J. Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma Investig. New Drugs 2020 38 831 843 10.1007/s10637-019-00840-1 31359240 PMC7211202

176. Good L. Benner B. Carson W.E. Bruton’s tyrosine kinase: An emerging targeted therapy in myeloid cells within the tumor microenvironment Cancer Immunol. Immunother. 2021 70 2439 2451 10.1007/s00262-021-02908-5 33818636 PMC8019691

177. Bao Y. Zheng J. Han C. Jin J. Han H. Liu Y. Lau Y.L. Tu W. Cao X. Tyrosine kinase Btk is required for NK cell activation J. Biol. Chem. 2012 287 23769 23778 10.1074/jbc.M112.372425 22589540 PMC3390651

178. Xia S. Liu X. Cao X. Xu S. T-cell expression of Bruton’s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia Cell. Mol. Immunol. 2020 17 1042 1052 10.1038/s41423-019-0270-9 31431692 PMC7608443

179. Liu Y. Dong Y. Jiang Q.L. Zhang B. Hu A.M. Bruton’s tyrosine kinase: Potential target in human multiple myeloma Leuk. Lymphoma 2014 55 177 181 10.3109/10428194.2013.794458 23581641

180. Richardson P.G. Bensinger W.I. Huff C.A. Costello C.L. Lendvai N. Berdeja J.G. Anderson L.D. Jr. Siegel D.S. Lebovic D. Jagannath S. Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: Phase 2 trial results Br. J. Haematol. 2018 180 821 830 10.1111/bjh.15058 29435979 PMC5873373

181. Hajek R. Pour L. Ozcan M. Martin Sánchez J. García Sanz R. Anagnostopoulos A. Oriol A. Cascavilla N. Terjung A. Lee Y. A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma Eur. J. Haematol. 2020 104 435 442 10.1111/ejh.13377 31883396 PMC7216833

182. Woyach J.A. Ibrutinib and Aspergillus: A Btk-targeted risk Blood 2018 132 1869 1870 10.1182/blood-2018-08-865659 30385492

183. Rogers K.A. Mousa L. Zhao Q. Bhat S.A. Byrd J.C. El Boghdadly Z. Guerrero T. Levine L.B. Lucas F. Shindiapina P. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies Leukemia 2019 33 2527 2530 10.1038/s41375-019-0481-1 31086260 PMC7425823

184. Chari A. Cornell R.F. Gasparetto C. Karanes C. Matous J.V. Niesvizky R. Lunning M. Usmani S.Z. Anderson L.D. Jr. Chhabra S. Final analysis of a phase 1/2b study of ibrutinib combined with carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma Hematol. Oncol. 2020 38 353 362 10.1002/hon.2723 32053229 PMC7496325

185. Ailawadhi S. Parrondo R.D. Moustafa M.A. LaPlant B.R. Alegria V. Chapin D. Roy V. Sher T. Paulus A. Chanan-Khan A.A. Ibrutinib, lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma: Phase I trial results Hematol. Oncol. 2022 40 695 703 10.1002/hon.3012 35488778

186. Neuzillet C. Tijeras-Raballand A. Cohen R. Cros J. Faivre S. Raymond E. de Gramont A. Targeting the TGFβ pathway for cancer therapy Pharmacol. Ther. 2015 147 22 31 10.1016/j.pharmthera.2014.11.001 25444759

187. Kyrtsonis M.C. Repa C. Dedoussis G.V. Mouzaki A. Simeonidis A. Stamatelou M. Maniatis A. Serum transforming growth factor-beta 1 is related to the degree of immunoparesis in patients with multiple myeloma Med. Oncol. 1998 15 124 128 10.1007/BF02989591 9789221

188. Malek E. Hwang S.J. Caimi P.F. Metheny L.L. Tomlinson B.K. Cooper B.W. Boughan K.M. Otegbeye F. Gallogly M. Driscoll J.J. Phase Ib trial of vactosertib in combination with pomalidomide in relapsed multiple myeloma: A corticosteroid-free approach by targeting TGF-beta signaling pathway J. Clin. Oncol. 2021 39 8039 10.1200/JCO.2021.39.15_suppl.8039

189. Prior I.A. Hood F.E. Hartley J.L. The frequency of Ras mutations in cancer Cancer Res. 2020 80 2969 2974 10.1158/0008-5472.CAN-19-3682 32209560 PMC7367715

190. Xu J. Pfarr N. Endris V. Mai E.K. Md Hanafiah N.H. Lehners N. Penzel R. Weichert W. Ho A.D. Schirmacher P. Molecular signaling in multiple myeloma: Association of RAS/RAF mutations and MEK/ERK pathway activation Oncogenesis 2017 6 e337 10.1038/oncsis.2017.36 28504689 PMC5523069

191. Schjesvold F. Ribrag V. Rodriguez-Otero P. Robak P.J. Hansson M. Hajek R. Amor A.A. Martinez-Lopez J. Onishi M. Gallo J.D. Safety and preliminary efficacy results from a phase Ib/II study of cobimetinib as a single agent and in combination with venetoclax with or without atezolizumab in patients with relapsed/refractory multiple myeloma Blood 2020 136 45 46 10.1182/blood-2020-135845

192. Sharman J.P. Chmielecki J. Morosini D. Palmer G.A. Ross J.S. Stephens P.J. Stafl J. Miller V.A. Ali S.M. Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma Clin. Lymphoma Myeloma Leuk. 2014 14 e161 e163 10.1016/j.clml.2014.06.004 24997557

193. Mey U.J.M. Renner C. von Moos R. Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation Hematol. Oncol. 2017 35 890 893 10.1002/hon.2353 27641727

194. Raje N. Chau I. Hyman D.M. Ribrag V. Blay J.Y. Tabernero J. Elez E. Wolf J. Yee A.J. Kaiser M. Vemurafenib in patients with relapsed refractory multiple myeloma harboring BRAF(V600) mutations: A cohort of the histology-independent VE-BASKET study JCO Precis. Oncol. 2018 2 1 9 10.1200/po.18.00070 PMC7446434 32913989

195. Pan D. Richter J. Where we stand with precision therapeutics in myeloma: Prosperity, promises, and pipedreams Front. Oncol. 2021 11 819127 10.3389/fonc.2021.819127 35127532 PMC8811139

196. Richardson P.G. Nagler A. Ben-Yehuda D. Badros A. Hari P.N. Hajek R. Spicka I. Kaya H. LeBlanc R. Yoon S.S. Randomized, placebo-controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib eJHaem 2020 1 94 102 10.1002/jha2.4 35847734 PMC9175725

197. Trudel S. Bahlis N.J. Venner C.P. Hay A.E. Biomarker driven phase II clinical trial of trametinib in relapsed/refractory multiple myeloma with sequential addition of the AKT inhibitor, GSK2141795 at time of disease progression to overcome treatment failure: A trial of the Princess Margaret phase II consortium Blood 2016 128 4526 10.1182/blood.V128.22.4526.4526

198. Tolcher A.W. Patnaik A. Papadopoulos K.P. Rasco D.W. Becerra C.R. Allred A.J. Orford K. Aktan G. Ferron-Brady G. Ibrahim N. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma Cancer Chemother. Pharmacol. 2015 75 183 189 10.1007/s00280-014-2615-5 25417902

199. Calimeri T. Ferreri A.J.M. m-TOR inhibitors and their potential role in haematological malignancies Br. J. Haematol. 2017 177 684 702 10.1111/bjh.14529 28146265

200. Gunther A. Baumann P. Burger R. Kellner C. Klapper W. Schmidmaier R. Gramatzki M. Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: A phase I study Haematologica 2015 100 541 547 10.3324/haematol.2014.116269 25682600 PMC4380728