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Novel Agents in Multiple Myeloma

Szalat, Raphaël, MD*†; Munshi, Nikhil C., MD*‡

doi: 10.1097/PPO.0000000000000355
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The therapeutic landscape of multiple myeloma (MM) has dramatically changed in the last 15 years with the advent of immunomodulatory drugs and proteasome inhibitors. However, majority of MM patients relapse, and new therapies are needed. Various agents with diverse mechanisms of action and distinct targets, including cellular therapies, monoclonal antibodies, and small molecules, are currently under investigation. In this review, we report novel drugs recently approved or under advanced investigation that will likely be incorporated in the future as new standard for MM treatment, focusing on their mechanisms of action, cellular targets, and stage of development.

From the *Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School;

Section of Hematology and Oncology, Boston Medical Center; and

VA Boston Healthcare System, Boston, MA.

The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Reprints: Nikhil C. Munshi, MD, Dana-Farber Cancer Institute, 44 Binney St, D1B06, Boston, MA, 02115. E-mail: Nikhil_Munshi@dfci.harvard.edu.

The advent of immunomodulatory drugs (IMids) and proteasome inhibitors (PIs) opened a new era in the therapy of multiple myeloma (MM) contributing to significant prolongation of survival. In the last 5 years, the Food and Drug Administration (FDA) approved 5 new drugs, pomalidomide (Pom) (an analog of lenalidomide [Len]), carfilzomib, ixazomib (2 new PIs), panobinostat (a pan–histone deacetylase [HDAC]), and 2 monoclonal antibodies (mAbs), daratumumab (Dara) (targeting CD38) and elotuzumab (targeting the signaling lymphocytic activation molecule F7 [SLAMF7]) (Table 1). One of the new and most exciting challenges is now to identify the most efficient combinations of these new agents in induction and maintenance regimen and to define the best therapeutic strategies according to risk stratification and patient characteristics.1 Nevertheless, a subgroup of high-risk patients remain characterized by poor survival despite these most recent available treatment combinations, and most patients continue to experience relapses, underlying the need for new active treatments to cure the disease.2

TABLE 1

TABLE 1

The study of MM genomics along with the discovery of new critical signaling pathways directing MM cell survival has allowed development of new and efficient therapeutic agents. Intracellular targets such as protein degradation, apoptosis pathway, and transcriptomic regulation are essential mechanisms of MM cell survival and represent new therapeutic avenues.3 In addition, the rise of immunotherapy with the development of mAbs directly targeting tumor cells such as Dara or isatuximab (anti-CD38 mAb) or elotuzumab (targeting SLAMF7),4,5 mAbs targeting immune checkpoints (such as pembrolizumab and nivolumab targeting programmed death 1 [PD-1]), and cellular therapies with chimeric antigen receptor T cells (CAR T cells) is now under critical evaluation in myeloma.6 In this review, we focus on the newest agents most recently approved or in advanced development in myeloma, excluding cellular immunotherapies and protein catabolism targeted therapies that are detailed elsewhere in this issue. For a matter of clarity, we present these new agents based on their mechanisms of action or therapeutic target (Table 2 and Table 3).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

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Antibodies Targeting MM Cells

Antimyeloma mAbs are humanized or chimeric antibodies targeting malignant plasma cells that can correspond to mAbs, drug-conjugated mAbs, or bispecific antibodies.

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Monoclonal Antibodies Targeting CS1

Elotuzumab is a humanized immunoglobulin G1 immunostimulatory mAb targeted against signaling lymphocytic activation molecule F7 (SLAMF7, also called CS1 [cell-surface glycoprotein CD2 subset 1]). SLAMF7 is a glycoprotein expressed on myeloma and natural killer (NK) cells.7,8 SLAMF7 belongs to the SLAM family on chromosome 1q23 and is highly expressed in MM cells independently of cytogenetic abnormalities. The binding of elotuzumab to SLAMF7 activates NK cells by coupling with its adapter protein EAT-2, whereas it leads to antibody-dependent cell cytotoxicity targeting MM cells as EAT-2 is not expressed in MM cells.9,10 Elotuzumab has modest impact as single agent in relapse or refractory MM (RRMM) as shown in a phase I study in 35 relapse and refractory MM, where 26.5% of the patients had stable disease, but no overall response was observed.11 However, considering the impact of IMids on the immune system, activating NK cells and inhibiting T cells regulators, several studies have combined elotuzumab with IMids and showed significant synergistic activity. In 2 phase I studies in RRMM combining elotuzumab either with bortezomib/dexamethasone (Dex) or with Len/Dex, the overall response rate (ORR) were 48 and 82% respectively.12,13 In the phase III clinical trial ELOQUENT 2,14 elotuzumab was evaluated in addition to Len and Dex in RRMM. The ORR in the elotuzumab group was 79%, versus 66% in the control group (P < 0.001), and the median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (P < 0.001). In another multicenter, randomized, open-label, phase II trial (ELOQUENT 3),15 MM patients refractory to Len and to a PI were treated with elotuzumab plus Pom and Dex or Pom/Dex alone. The ORR was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% confidence interval [CI], 1.49–7.11). The median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group. The risk of progression or death was significantly lower among those who received elotuzumab. Importantly, the combination of elotuzumab with Len or Pom and Dex was not associated with an increased toxicity.

Conversely, combining elotuzumab with bortezomib did not show significant benefit in a phase II clinical trial, although overall survival and PFS tended to be increased.16 Elotuzumab was approved in combination with Len in RRMM in the United States in November 2015 and in Europe in May 2016 and in combination with Pom in November 2018. An ongoing phase III clinical trial (ELOQUENT 1, NCT01335399) is evaluating elotuzumab combined with Len/Dex versus Len/Dex alone in newly diagnosed elderly or unfit patientsnon eligible for autotransplant, and a similar combination is also evaluated in high-risk smoldering MM patients (NCT02279394).

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Monoclonal Antibodies Targeting CD38

CD38 is a 45-kDa transmembrane glycoprotein that links with cell-surface receptors in lipid rafts, regulates cytoplasmic Ca2+ flux, and mediates signal transduction in lymphoid and myeloid cells.17 CD38 is highly expressed on myeloma cells, while its expression is low on normal lymphoid and myeloid cells and in some tissues of nonhematopoietic origin.18

Daratumumab is a human immunoglobulin G1κ (IgG1κ) mAb that binds to a unique CD38 epitope.19 Preclinical studies showed that activity of Dara is mediated by multiple mechanisms including complement-mediated and antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis, and inhibition of the enzymatic activity of CD38.20 In 2 phase I/II clinical trials, Dara was tested as a single agent in RRMM.21 In one study, the ORR was 36% in the cohort receiving 16 mg/kg, and 65% (95% CI, 28%–86%) of the patients who had a response did not have progression at 12 months.21 In the second study, overall responses were noted in 29% (95% CI, 20.8%–38.9%), median duration of response was 7.4 months (95% CI, 5.5 months to not estimable), and progression-free survival was 3.7 months (95% CI, 2.8–4.6 months). The 12-month overall survival was 64.8% (95% CI, 51.2%–75.5%) (SIRIUS trial).22

Subsequently, Dara was used in combination with either bortezomib/Dex23 or Len/Dex24 in 2 phase III clinical trials.23,24 In the phase III clinical trial23 comparing Bortezomib/Dex to Bortezomib/Dex/Dara in 498 RRMM patients (Castor trial), the 12-month rate of progression-free survival was 60.7% in the Dara group versus 26.9% in the control group. The rate of overall response was higher in the Dara25 group than in the control group as well (82.9% vs. 63.2%, P < 0.001), as were the rates of complete response or better (19.2% vs. 9.0%, P = 0.001). After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the Dara group and was 7.2 months in the control group (hazard ratio for progression or death with Dara vs. control, 0.39; 95% CI, 0.28–0.53; P < 0.001). In the phase III clinical trial comparing Len/Dex to Dara/Len/Dex (Pollux trial) in 569 RRMM patients, the progression-free survival at 12 months was 83.2% (95% CI, 78.3%–87.2%) in the Dara group, as compared with 60.1% (95% CI, 54.0%–65.7%) in the control group. A significantly higher rate of overall response was observed in the Dara group than in the control group (92.9% vs. 76.4%, P < 0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P < 0.001). In the Dara group, 22.4% of the patients had results below the threshold (1 tumor cell per 105 white cells) for minimal residual disease (MRD), as compared with 4.6% of those in the control group (P < 0.001); results below the threshold for MRD were associated with improved outcomes.

As upfront therapy, Dara has been evaluated in patients ineligible for autotransplant in a phase III clinical trial comparing bortezomib, melphalan, and prednisone (MPV) either alone (control group) or with Dara (ALCYONE clinical trial).26 At a median follow-up of 16.5 months, the 18-month progression-free survival rate was 71.6% in the Dara group and 50.2% in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38–0.65; P < 0.001). The ORR was 90.9% in the Dara group, as compared with 73.9% in the control group (P < 0.001), and the rate of complete response or better (including stringent complete response) was 42.6% versus 24.4% (P < 0.001). In the Dara group, 22.3% of the patients were negative for MRD (at a threshold of 1 tumor cell per 105 cells), as compared with 6.2% of those in the control group (P < 0.001). Daratumumab is now approved by the FDA since 2016.

Isatuximab (SAR650984) is another chimeric IgG1 mAb made by variable domain resurfacing, targeting a different amino acid sequence epitope of CD38 than Dara. In addition, isatuximab has a direct toxic effect on MM cells as well.27,28 Initial data suggest that isatuximab has clinical activity as a single agent, with an ORR of 32% obtained in patients with RRMM.29 Isatuximab, in combination with Len/Dex has been evaluated in a phase Ib clinical trial in 57 RRMM patients. The ORR30 was 56% (29/52), and 52% in evaluable Len-refractory patients.31 Isatuximab is currently being evaluated in RRMM as a single agent or with Dex (NCT01084252) and in combination with Revlimid (lenalidomide)/Velcade (bortezomib)/ Dexamethasone in newly diagnosed patients (NCT02513186). Efficacy of isatuximab in patients relapsing after Dara will be interesting as both target slightly different epitopes on CD38 molecule.

A third anti-CD38 mAb (MOR202)32 is also in early clinical trials, and bispecific antibodies targeting CD38 and CD3 (AMG 424)33 and a mAb conjugated with α-emitter astatine-211 (211At), an α-particle emitting isotopes,34,35 are also being evaluated in early phase clinical trial and preclinical models.

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Monoclonal Antibodies Targeting B-Cell Maturation Antigen

B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily (TNFRSF17), is selectively induced during plasma cell differentiation and nearly absent on naive and memory B cells and CD34-positive hematopoietic stem cells. BCMA is highly expressed in MM cells. B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL)36 are 2 known ligands of BCMA that induce survival of long-lived plasma cells. Significantly, soluble BCMA levels are increased in MM patients in comparison to healthy individuals and correlate with disease status and prognosis. These data have highlighted BCMA as a very promising target in MM. Several mAbs and cellular therapies targeting BCMA are under investigation including mAbs, antibody-drug conjugate, and bispecific antibodies.37

GSK2857916 is humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker, which specifically blocks cell growth via G2/M arrest and induces caspase 3–dependent apoptosis.38 In an international, multicenter, open-label, first-in-human phase I/II study, 73 patients—38 patients with RRMM in the dose-escalation part 1 and 35 patients in the dose-expansion part 2—were treated. There were no dose-limiting toxicities, and maximum tolerated dose was not identified in part 1. In part 2, 21 (60%; 95% CI, 42.1%–76.1%) of 35 patients achieved an overall response suggesting a promising role of this conjugated mAb. Of note, corneal events were common (53% of 38 patients in part 1 and 63% of 35 in part 2) but moderate in majority. The most common other grade 3 or 4 events were thrombocytopenia (13 [34%] of 38 patients in part 1 and 12 [34%] of 35 in part 2) and anemia (6 [16%] in part 1 and 5 [14%] in part 2). There were 12 treatment-related serious adverse events and no treatment-related deaths. Other antibody-conjugated targeting BCMAs are under investigation such as HDP-1, an antibody-amanitin conjugate, or MeDi2228, a fully human antibody—specifically conjugated to a pyrrolobenzodiazepine dimer via a protease-cleavable linker.39,40

Bispecific mAbs targeting BCMA are also being actively developed. BI 836909, a bispecific single-chain variable fragment (scFv) that simultaneously binds to CD3 and BCMA, was the first reported. Preclinical evaluation was promising in mouse and monkeys, and further investigations are ongoing, although the short half-life of the molecule might require frequent infusions.41 Several other bispecific antibodies are under development and include TNB383B, TNB-384B, Ab-957, EM801, and BCMA-TCB2, which are also IgG-based human bispecific antibodies with 2 binding sites for BCMA and CD3 with significant toxicity on MM cells in preclinical models.25,42,43 PF-3135 is a humanized IgG2a CD3 and BCMA-bispecific mAb that is now being evaluated in an ongoing phase I clinical trial (NCT03269136).44 AFM26 is a bispecific antibody, which targets BCMA and CD16A on NK cells with significant efficacy in preclinical models. Its impact on NK cells suggest a potential for a synergistic activity with IMids.45 Finally, trispecific antibody-like molecules targeting BCMA are also under evaluation. An anti-CD16A/BCMA/CD200 antibody binding to CD16A on NK cells and to BCMA and CD200 on MM cells with potentially significant efficiency and increased selectivity of MM cells is under evaluation.46

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Monoclonal Antibodies Targeting APRIL

A proliferation-inducing ligand36 is one of the 2 known ligands of BCMA, and its binding to BCMA enhances plasma cell proliferation and survival. BION-1301 is a humanized anti-APRIL antibody blocking the binding of APRIL to BCMA and TACI that has significant impact in vitro and in coculture models and currently evaluated in an early phase clinical trial in RRMM (NCT03340883).

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Monoclonal Antibodies Targeting CD138

Indatuximab ravtansine (BT062) is a mAb-drug conjugate under development targeting CD138 (syndecan1), which is universally highly expressed on MM cells. The mAb is coupled to the maytansinoid DM4 toxin. In a phase I/II clinical trial evaluating BT062 in combination with Len/Dex or Pom/Dex in RRMM, promising preliminary results were observed with ORRs of 54% and 79%, respectively, in each arm.47,48

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Monoclonal Antibodies Targeting Immune Checkpoints

The advent of immune checkpoint inhibitors is one of the most important progress in the last few years in oncology. The development of mAbs targeting the immune checkpoints has considerably changed the treatment and prognosis of several cancers including melanoma, lung cancer, and relapsed and refractory Hodgkin disease, among others. In MM, PD-1 receptor (PD-L1 or PD-L2) is highly expressed, suggesting that treatment targeting it or its ligand would be an effective strategy.49 Several mAbs targeting PD-1 (pembrolizumab, nivolumab) or PD-L1 (durvalumab, atezolizumab) are approved for various other malignancies.50 Based on promising phase II data with the combination of pembrolizumab with Pom/Dex and Len/Dex in RRMM, 3 phase III clinical trials—KEYNOTE-183 and KEYNOTE-185 and CheckMate 602—respectively evaluated Pom/Dex with or without pembrolizumab in RRMM, Len/Dex with and without pembrolizumab in newly diagnosed MM patients noneligible for autotransplant, and nivolumab plus Pom–Dex versus Pom–Dex alone or Pom/Dex/elotuzumab/nivolumab in patients with RRMM. All studies were stopped prematurely because of an increased mortality in patients receiving pembrolizumab with a hazard ratio for death of 1.61 in KEYNOTE-183 and 2.06 in KEYNOTE-185, or nivolumab in CheckMate 602 (hazard ratio for death was 1.19; 95% CI, 0.64–2.20). Furthermore, the addition of pembrolizumab or nivolumab did not increase the ORR. Importantly, no specific cause of death was observed in all 3 trials, and the pathogenesis behind the toxicity of the combination remains largely unknown as well as the absence of obvious efficacy of the mAbs. These results have raised serious doubts regarding their utility in MM at least in combination with the immunomodulatory agents.51 However, other immune checkpoints such as LAG3, TIM3, or TIGIT are under preclinical investigation.52–55

Various other cell-surface molecules have been targeted using antibodies, which have undergone promising preclinical evaluation (Table 2).

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DNA Damaging Agents

Alkylating agents remain a cornerstone of MM treatment with high-dose melphalan as the conditioning regimen of choice for autotransplant. New alkylating agents have been developed in order to improve efficacy and decrease toxicity of DNA-damaging agents.

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Melflufen

Melphalan flufenamide ethyl ester (melflufen) is a peptidase-potentiated alkylating agent that appears to be more efficient than melphalan.56 Especially, in vitro evaluation showed that melflufen is active in melphalan-resistant cell lines by generating rapid and irreversible DNA damage. Three clinical trials are ongoing to confirm its efficacy in MM. The phase II clinical trial 012M1 evaluating melflufen in RRMM with at least 2 prior lines of therapy including bortezomib and Len showed promising results with an ORR of 31% in advanced RRMM patients.57 The phase II clinical trial HORIZON evaluating melflufen in RRMM with at least 2 prior lines of treatment including IMids, PI, Pom, and Dara showed an ORR of 27%. A clinical phase III trial comparing melflufen versus Pom in RRMM and a phase I/II trial combining melflufen with bortezomib and Dara in RRMM are ongoing and will likely confirm the role of this new alkylating agent in MM.58,59

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Bendamustine

Bendamustine is an alkylating agent with a purine analog ring that has been developed several decades ago, although its cautious evaluation in MM is more recent.60 A phase III clinical trial that compared bendamustine + prednisone with melphalan + prednisone in newly diagnosed patients ineligible for autotranplant showed a benefit especially in terms of time to progression (TTP) (14 vs. 10 months).61 Several phase II clinical studies combining bendamustine with PI or IMids have been reported with relatively good results, making bendamustine as an available additional therapeutic option.62–65

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EDO-S101

Preclinical data suggested a synergism between alkylating agents and histone deacetylase inhibitors, although their combination in patients was associated with important toxicity.66–68 EDO-S101 is a first-in-class fusion molecule derived from bendamustine that has been linked to a class 1 and 2 HDACi, now under preclinical evaluation.69

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Inhibitors of BCL2 Family Proteins

Important efforts in research have been made to understand the mechanisms driving cancer cell survival. In the last 2 decades, significant discoveries have shed light on the mechanisms regulating apoptosis in cancer cells. The BCL2 family proteins have been identified as critical regulators of apoptosis in cancer and healthy tissues. This family includes Bcl-2, Bcl-XL, and Mcl-1, which are multidomain antiapoptotic proteins. Several groups have identified a tissue-specific antiapoptotic dependency, and small molecules have been developed to target the BCL2 family proteins.70 Interestingly, bcl2 dependency can be assessed functionally with a method using BH3 profiling, a flow cytometry–based method, or simply by evaluating the levels of expression of BCL2, bcl-xl, and MCL1.71,72

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Venetoclax

Venetoclax (ABT-199) has been approved for several hematologic malignancies in the past few years including chronic lymphoid leukemia and mantle cell lymphoma. In MM, venetoclax has been shown to be active in RRMM as a single agent in a phase I clinical trial.73

Importantly, the presence of t(11;14) in MM confers a higher BCL2 dependency, and prolonged, deep responses have been observed in the subgroup of t(11;14) MM, which comprise ~20% of MM patients. In this trial, the ORR in patients with t(11;14) translocation was 40%, including 14% complete response or better.30 In the non-t(11;14) group, 2 patients (6%) achieved at least a partial response. The phase II M13-367 study (NCT01794520) is currently evaluating the efficacy of venetoclax (800 mg daily) in combination with Dex in relapsed myeloma patients with t(11;14) translocation. Preliminary results revealed an ORR of 65%, including 35% VGPR in advanced relapsed MM patients (median of 3 prior therapies).

Venetoclax in combination with other agents has also shown efficacy in non-t(11;14) MM. Especially, bortezomib and other PIs have been shown to indirectly inhibit MCL-1 and potentially synergistic activity with venetoclax. Thus, in a phase II clinical trial evaluating venetoclax/bortezomib/Dex in 66 RRMM patients, the ORR30 was 67% (44/66). Overall response rate of 97% and very good partial response 73% or greater were seen in patients not refractory to bortezomib who had 1 to 3 prior therapies. Patients with high BCL2 expression had a higher ORR (94%).74

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MCL1 Inhibitors

With success of targeting BCL2, other antiapoptotic molecules involved in MM cell survival are being evaluated as potential targets. MCL1 inhibitors are the second most advanced drugs in development. Currently, a phase II clinical trial is ongoing to evaluate safety and efficacy of MCL1 inhibitor in MM using MIK665 (NCT02992483) and AMG 176 (NCT02675452).

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Epigenetic Inhibitors

Histone Deacetylase

Epigenetic mechanisms play a critical role in deregulating MM cells transcriptome and enhancing tumor progression.75–77 Histone deacetylases include 4 classes of proteins according to their structure and function: class I (HDAC 1, 2, 3, and 8), class IIa (HDACs 4, 5, 7, and 9), class IIb (HDACs 6 and 10), class III (sirtuins), and class IV (HDAC11). Pan-HDAC inhibitors have been the first molecules tested and developed in MM. While a modest impact has been shown in monotherapy, the role of HDAC in disrupting aggresomal protein degradation led to evaluation of the efficiency of HDAC in combination with PIs. Thus, panobinostat (a pan-HDAC inhibitor) combined with bortezomib has been approved by the FDA as a third line treatment in patients previously treated with IMids and PIs. This was based on a phase III clinical trial confirming efficacy in the setting of RRMM with a four month improvement in event free survival.78 A challenge resulting from pan-HDAC inhibition is the lack of specificity and the adverse effects observed that often lead to treatment discontinuation. For this reason, selective HDAC inhibitors are now under investigation. Particularly, a HDAC6 inhibitor (ricolinostat) is now investigated in clinical trials, and a phase Ib study showed that RRMM patients treated with ricolinostat plus bortezomib/Dex had a 37% ORR in RRMM.79 Another phase Ib trial showed a promising ORR of 55% when ricolinostat was combined with Len/Dex in RRMM with limited toxicity.80

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EZH2 Inhibitors

Various epigenetic modifiers are altered in MM including overexpression of enhancer of zeste homolog 2 (EZH2) or MMSET overexpression and UTX/KDM6A mutations.81,82 EZH2 is a histone methyltransferase, component of polycomb repressive complex 2, which triggers H3K27me3 to repress gene transcriptome; MMSET is a histone methyltransferase that regulates gene expression through H3K36 methylation; and UTX regulates H3K27 acetylation. MMSET is overexpressed in t(4;14), which represents ~15% of MM and is associated with high-risk disease. UTX/KDM6A mutation is observed in up to 5% of MM patients. UTX loss and MMSET overexpression are associated with increased transcriptomic control by EZH2.83 Recent advances include development of small molecule inhibitors of EZH2, which have shown significant efficacy against MM cells in vitro.84–86 Tazemetostat, an oral EZH1/2 inhibitor, is under preclinical evaluation in hematologic malignancies. Alternatively, important efforts have been made to develop MMSET inhibitors to generate targeted therapy in this subgroup of patients, but the improvements in bioavailability and specificity of the drugs are still in preclinical development.

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Mitogen-Activated Protein Kinase Pathway Inhibitors

Trametinib

Unlike other malignancies characterized by recurrent genomic driver such as MYD88 in Waldenström disease or BRAF V600E mutation in melanoma or hairy cell leukemia, MM is featured by a highly heterogeneous genetic background that includes various subtypes without clearly defined drivers. Only few recurrent mutations have been identified (NRAS, KRAS, TP53, DIS3, and FAM46C), with nuclear factor κB and mitogen-activated protein kinase (MAPK) pathways being the most recurrently affected pathways, in 14% and 50% of MM patients, respectively.87 For this reason, the MAPK pathway is an attractive target in MM. Vemurafenib as single agent or in combination with bortezomib has been reported as active in V600EBRAF mutated MM patients,88,89 but this mutation is present in only 2% to 5% of MM patients and is not systematically screened.87 MEK inhibition using trametinib or in combination with dabrafenib could represent interesting therapeutic option. A first retrospective study reported potential benefit of trametinib as a single agent or in combination with other MM approved treatment.90 However, patients were heavily treated and presented with very advanced disease, and toxicity was a concern (24/58 patients discontinued therapy because of toxicities).90 In addition, this study did not select patients based on presence of perturbation in MAPK pathway, and thus its real role in possibly susceptible patient population will be determined by ongoing studies utilizing trametinib and dabrafenib in targeted patient population. Alone or in combination, these agents may become an important and efficient therapeutic strategy in MM.

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Afuresertib

Afuresertib is an oral AKT inhibitor. That has been evaluated in 2 phase I clinical trials in RRMM as a single agent and in combination with bortezomib and Dex. As a single agent, afuresertib showed limited activity, but when combined with bortezomib and Dex, the ORR was up to 61%.91,92 In another phase I study, afuresertib has been combined to trametinib and evaluated in MM and solids tumors, but the toxicity was high, and the study was discontinued.93

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Inhibitors of Nuclear Cytoplasmic Transport Receptor: XPO1 Inhibitor

The ubiquitous transport receptor chromosome maintenance protein 1 (CRM1, also known as XPO1) is a nuclear-cytoplasmic transport receptor that acts as a carrier molecule enhancing transportation into (importins) and out of (exportins) the nucleus. XPO1 is a member of the karyopherin family, which includes 19 members. XPO1 mediates the nuclear export of RNAs, and a large number of proteins carrying a canonical hydrophobic leucine-rich amino acid sequence, some transcription factors involved in nuclear factor κB signaling, and HDACs.94 XPO1 expression is high in MM cells and correlates with survival in MM patients suggesting a critical role in MM biology.

Selinexor (KPT-330) is a first-in-class, orally bioavailable, selective inhibitor of XPO1-mediated nuclear export. A phase I study evaluated selinexor alone or in combination with low-dose Dex and showed broad activity and promising response in RRMM. Two phase II clinical trials recently published evaluated selinexor and Dex and selinexor in combination with bortezomib and Dex in heavily pretreated RRMM patients. In the first study evaluating selinexor/Dex, the ORR was 21% in all patients and 35% in high-risk patients, whereas the ORR was 63% for PI-nonrefractory and 43% for PI-refractory patients in the study evaluating the combination of bortezomib/selinexor/Dex. Both studies showed good response with limited toxicity and confirmed sleinexor as a promising novel agent in MM.95,96

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Immunomodulatory Drugs

Approved IMids in MM include thalidomide, Len, and Pom. These molecules share an antimyeloma activity that relates to its interaction with the intracellular complex cereblon/E3 ubiquitin ligase/Cul4A/DDb1. This binding enhances the degradation of 2 key transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) through the proteasome and block MM cell proliferation and growth. In addition, IMids enhance cell activation of various immune cells including NK, CD4, and CD8 T cells while inhibiting regulatory T cells.97,98 Therefore, IMids have synergistic activity with other immunotherapies such as mAbs or checkpoint inhibitors. Two new IMids CC220 (or iberdomide) and CC-92480, harboring greater affinity for the cereblon/Cul4a/E3ligase complex and degradation of its substrate, are now under investigation in various hematologic malignancies including MM.99

In addition, the understanding of the mechanism of action of the IMids has allowed for development of a new class of drugs that are currently in preclinical stage. This class of drugs called degraders uses the properties of IMids to bind to the cereblon/e3ligase/Cul4a complex to degrade specific targets.100

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Kinesin Spindle Protein Inhibitor

Filanesib (ARRY-520) is a kinesin spindle protein inhibitor, with clinical activity as monotherapy in heavily pretreated MM patients. Kinesin spindle protein (EG5/KIF11) is a critical molecule in cell division by contributing to the spindle apparatus and centrosome formation during mitosis.101

In a phase I study, Arry-520 was tested in heavily pretreated RRMM and was associated with an ORR of 16% with a tolerable safety.102 Several ongoing phase II clinical trials are evaluating ARRY-520 in combination with Pom/Dex (NCT02384083), bortezomib/Dex (NCT01248923), or carfilzomib/Dex (NCT01372540) in RRMM and plasma cell leukemia.

The identification of new therapeutic targets in MM along with the rise of immunotherapy and small molecule inhibitors provide significant change in MM therapeutic landscape. Several new molecules have recently been approved, and several other therapies referenced in this review will likely be soon validated too. Altogether, with the advent of cellular therapies discussed in a separate article in this issue, these novel agents will deeply modify the course of MM and eventually allow for a curative outcome in this disease. The detection of MRD by either next-generation flow cytometry or next-generation sequencing will likely be used as a new surrogate marker to monitor the disease and guide therapy while incorporating all these new efficient agents.

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Keywords:

IMids; multiple myeloma; proteasome inhibitors

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