Expert Opinion on Investigational Drugs

 

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New drugs in early development for treating multiple myeloma: all that glitters is not gold

Luca Bertamini , Francesca Bonello , Mario Boccadoro & Sara Bringhen

To cite this article: Luca Bertamini , Francesca Bonello , Mario Boccadoro & Sara Bringhen (2020): New drugs in early development for treating multiple myeloma: all that glitters is not gold, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2020.1772753
To link to this article: https://doi.org/10.1080/13543784.2020.1772753

Accepted author version posted online: 20 May 2020.

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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Opinion on Investigational Drugs

DOI: 10.1080/13543784.2020.1772753

New drugs in early development for treating multiple myeloma: all that glitters is not gold

Luca Bertamini1*, Francesca Bonello1*, Mario Boccadoro1 and Sara Bringhen1

1Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria Città della Salute e della Scienza di Torino, Torino, Italy

*These authors equally contributed to this article and share the first authorship.

Corresponding author: Dr. Sara Bringhen, MD, PhD, Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, via Genova 3 -10126 Torino, Italy. Tel +39 011 6333 4301, Fax: +39 011 63334187, e- mail: [email protected]
ORCID ID: 0000-0003-4539-6363

Abstract

Introduction. The last twenty years have introduced new therapeutic agents for multiple myeloma (MM); these include proteasome Inhibitors (PIs), immunomodulatory drugs (IMDs) and monoclonal antibodies (mAbs). However, MM remains incurable, hence there is an unmet need for new agents for the treatment of advanced refractory disease. New agents could also be used in early lines to achieve improved, more sustained remission.
Areas Covered. We review the most promising agents investigated in early-phase trials for the treatment of MM and provide an emphasis on new agents directed against well-known targets (new PIs, IMDs and anti-CD38 mAbs). Drugs that work through distinct and numerous mechanisms of action (e.g. pro-apoptotic agents and tyrosine kinase inhibitors) and innovative immunotherapeutic approaches are also described. The paper culminates with our perspective on therapeutic approaches on the horizon for this disease.
Expert opinion. IMD iberdomide and the export protein inhibitor selinexor demonstrated efficacy in heavily pretreated patients who had no other therapeutic options. We expect that immunotherapy with anti-BCMA BTEs and ADCs will revolutionize the approach to treating the early stages of the disease. Data on venetoclax in t(11;14)-positive patients may pave the way for personalized therapy.

Keywords: multiple myeloma, new drugs, early development, proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, small proteins, immunotherapy

Article Highlights

• Finding novel, successful treatments for advanced refractory multiple myeloma is crucial. The introduction of new agents in early lines of therapy could improve patient response in terms of depth and duration.
• New agents exploiting well-known mechanisms of action, such as the new immunomodulatory drug iberdomide (CC-220), showed efficacy in heavily pretreated patients and appear promising for the earlier phase of the disease.
• Among the small molecules, venetoclax in patients carrying t(11;14) and selinexor showed great potential, although concerns arose about their safety profiles.
• The new anti-CD38 monoclonal antibody MOR202 revealed a good tolerability and a promising efficacy in combination with immunomodulatory drugs, and answers about its possible role in the daratumumab and isatuximab era will be provided by larger randomized trials.
• Among the antibody-drug conjugates, the anti-B-Cell maturation antigen (anti-BCMA) belantamab mafodotin is in the spotlight and showed efficacy also in daratumumab- refractory patients. Nonetheless, ocular toxicity could be an issue for its long-term use.
• Anti-BCMA-CD3 bispecific T-cell engagers have induced deep responses in heavily pretreated patients, who in some cases achieved minimal residual disease negativity. Moreover, toxicities related to cytokine release syndrome and the central nervous system seemed to be less burdensome compared to those of CAR-T therapy.

 Introduction

Multiple myeloma (MM) is the second most common hematologic malignancy, with an incidence of 6.9:100000 people per year and has traditionally been considered an incurable disease [1]. In the past few years, the prognosis of MM patients has improved significantly with the introduction of novel agents such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMDs) [2,3]. Immunotherapy revolutionized the disease course, with monoclonal antibodies (mAbs) such as daratumumab recently entering the clinical practice, and active immunotherapy with CAR-T and BTEs showing extraordinary preliminary results in patients refractory to all available treatments [4]. Although these agents are a step forward in the quest for MM cure, relapses still occur, and eventually patients become refractory to all treatments. Several novel agents and combinations are under clinical evaluation to further improve the prognosis of MM patients. Some of them exploit well-known mechanisms of action, such as new IMDs and anti-CD38 mAbs, but hold different features that could overcome the resistance to other agents of the same class. Other molecules have completely different targets, and could be combined with PIs, IMDs and mAbs to achieve deeper responses. Many agents are still under evaluation in phase I/II trials, and most of them will not be evaluated in randomized phase III studies due to lack of efficacy or safety concerns. It is fundamental to identify which agents may potentially make a difference in the MM treatment scenario. This review focuses on novel agents under evaluation in early-phase trials, providing insights on their clinical activity, safety profile and possible applications.
2. New drugs for old targets
2.1 New-generation PIs

The proteasome is a multienzyme complex that recognizes intracellular aberrant or unnecessary proteins and mediates their degradation through three different catalytic subunits. Proteasome activity is upregulated in MM cells, allowing tumor cells proliferation
and survival [5,6]. PIs are a cornerstone of MM treatment. Besides 3 approved agents
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(bortezomib, carfilzomib and ixazomib), new molecules are under clinical evaluation. The development of new PIs has the aim of introducing agents active in bortezomib/carfilzomib- refractory patients, with different safety profiles (e.g. limited neurological or cardiovascular side effects) and, possibly, with convenient schedules of administration. Oprozomib is an irreversible epoxyketone PI analog of carfilzomib that possesses the substantial feature of being orally available [7,8]. In a preliminary phase I/II trial on relapsed/refractory (RR)MM patients, single-agent oprozomib was evaluated, showing substantial activity with an overall response rate (ORR) of 25-41% depending on the schedule, including responses in bortezomib-refractory patients (ORR 18-31%). However, concerns arose about its safety profile. Gastrointestinal toxicity (mainly diarrhea and nausea of grade [G]≥3 up to 33% and 37%, respectively) was common, including 2 deaths for gastrointestinal hemorrhage at the maximum tolerated dose (MTD) during phase II. About 40% of patients discontinued treatment for adverse events (AEs) [9]. Subsequent trials evaluated different oprozomib formulations and the addition of dexamethasone, which seemed to improve tolerability. Oprozomib-dexamethasone was administered to RRMM patients with a median of 2 previous lines of therapy including bortezomib and lenalidomide. Despite the encouraging efficacy (ORR 58.7%, median progression-free survival [PFS] 9.1 months), toxicity was again a significant issue (G≥3 diarrhea 24-32%, nausea 9-32%, depending on the schedule) and the enrollment was interrupted [10]. Another study evaluated oprozomib with pomalidomide- dexamethasone (Pd) in heavily pretreated RRMM patients. With the schedule of the expansion phase, ORR was 71% and G≥3 AEs were limited (neutropenia 35%, thrombocytopenia 29%, diarrhea 12%, pneumonia 12%) [11]. Oprozomib was evaluated in newly diagnosed (ND)MM transplant-ineligible patients in combination with lenalidomide-dexamethasone (Rd), cyclophosphamide-dexamethasone or melphalan-prednisone. However, these trials were prematurely interrupted due to safety concerns and the extreme variability of pharmacokinetic characteristics of the formulation [12]. Currently, no further clinical development of oprozomib is occurring, due to its significant toxicity issues. New formulations could be evaluated to improve pharmacokinetics and gastrointestinal tolerability [12].
Marizomib is an irreversible PI that, differently from the other agents of this class, inhibits all three catalytic activities of the proteasome, suggesting its activity in MM cells that are resistant to other PIs [13]. Among PIs, marizomib has the unique feature of crossing the
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blood-brain barrier [14]. A preliminary phase I trial evaluated the triplet marizomib-Pd in 38 RRMM patients. ORR was 53%, including 6% of very good partial response (VGPR), with a median PFS of 4 months. Marizomib-Pd was well tolerated, with the main G≥3 AE being neutropenia (29%). This combination could be further investigated by testing higher doses of marizomib, since the agent showed activity and did not add significant toxicity to Pd. Interestingly, marizomib was evaluated in 2 MM patients with involvement of the central nervous system (CNS), improving their symptoms and reducing plasma cells in the cerebrospinal fluid. This provides the rationale for exploring marizomib in this rare subset of patients [15].
2.2 New-generation IMDs

IMDs represent the backbone of many standard-of-care treatments for NDMM and RRMM. Three IMDs are currently approved for clinical practice: thalidomide and its derivatives lenalidomide and pomalidomide. IMDs are so called because of their ability to modulate immune cell functions (mainly lymphocytes) through their activation and secretion of cytokines [16]. The biological target of IMDs is CRBN E3 ligase complex, which normally induces the ubiquitination and degradation of transcription factors known as IKZF1 (Ikaros) and IKZF3 (Aiolos), which are important for the normal differentiation of B and T lymphocytes and plasma cells via the downregulation of IRF4 and c/Myc [17–21]. Moreover, IKZF3 regulates the production of IL-2 by T cells [18]. The inhibition of these transcription factors is crucial to stop MM cell proliferation and modulate bone marrow microenvironment.
New-generation IMDs have recently been designed aiming at improving efficacy and overcoming lenalidomide and pomalidomide resistance. In preclinical analyses, iberdomide, also known as CC-220, enhanced the degradation of IKZF1 and IKZF3, revealing a greater antiproliferative effect than pomalidomide and lenalidomide also at lower concentrations. This is likely due to an increased affinity to CRBN and an improved activity of the E3 ligase when bound to iberdomide [22]. There is also evidence of a synergistic effect of iberdomide with bortezomib, dexamethasone and daratumumab in MM cell lines [22,23].
First data on iberdomide came from a phase I/II dose escalation study in RRMM patients who already received ≥2 prior therapies including lenalidomide or pomalidomide and a PI. In the first part of the trial, iberdomide was administered as monotherapy and in combination with
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dexamethasone, daratumumab-dexamethasone, carfilzomib-dexamethasone (Kd) and bortezomib-dexamethasone (Vd). The second part was a dose expansion aiming at highlighting the efficacy of iberdomide combined with dexamethasone.
Data presented so far are related to the administration of iberdomide-dexamethasone to 58 patients with 5 median prior lines of therapy. A total of 72% of patients experienced a G≥3 AE, mainly neutropenia (26%) and thrombocytopenia (11%). The discontinuation rate due to AEs was 5%. ORR was 27%, and 44% of patients had at least a minimal response (MR) [24]. The dose expansion phase and the cohorts with PIs and daratumumab are ongoing.
Avadomide (CC-122) is another thalidomide derivative, with a broad spectrum of action on MM and diffuse large B-cell lymphoma (DLBCL) cells [25]. A phase I study in patients with MM, non-Hodgkin’s lymphoma and solid tumors was conducted. Thirty-four patients were treated with a tolerable safety profile. One of the 2 MM patients achieved a stable disease (SD) [26]. CC-92480 showed promising preclinical activity on MM cell lines [27]; a phase I trial (NCT03374085) is ongoing on RRMM patients.
2.3 Melflufen

Melflufen (melphalan-flufenamide) is a melphalan-containing prodrug characterized by a high lipophilicity, which allows its rapid internalization into cells. Once inside the cell, this compound is hydrolyzed by aminopeptidases, a family of enzymes over-expressed in MM cells, allowing melphalan to elicit its alkylating cytotoxic activity [28]. Preclinical findings suggested a higher tumor-killing effect of melflufen, as compared to melphalan. This is likely related to the higher intracellular concentration obtained with this compound [29,30]. Activity has also been reported in melphalan-resistant cells in preclinical models [31].
A preliminary phase I/II trial evaluated melflufen-dexamethasone in RRMM patients (4 median prior lines). At the MTD, the ORR was 41%, and median PFS and OS were 5.7 and 20.7 months, respectively. The most common G3-4 toxicities were hematologic (thrombocytopenia 62%, neutropenia 58%) [32,33]. Melflufen demonstrated activity also in RRMM patient refractory to pomalidomide and/or daratumumab. Remarkably, activity was also observed among triple-refractory patients (refractory to at least 1 IMD, 1 PI and 1 anti-CD38 mAb), with an ORR of 20% [34]. In patients with extramedullary disease, who currently represent an unmet clinical need, melflufen induced an ORR of 20% [35]. The phase III OCEAN trial
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comparing melflufen-dexamethasone to Pd is ongoing, and expected results might lead to the approval of this agent for the treatment of RRMM [36]. Melflufen-dexamethasone in combination with daratumumab or bortezomib is showing encouraging efficacy and manageable toxicity in preliminary reports (ORR >80%) [37].
3. Small molecules
Results of the main phase I/II clinical trials with small molecules on RRMM patients are summarized in Table 1; main mechanisms of action are shown in Figure 1.
3.1 Targeting the anti-apoptotic pathway: venetoclax and MCL-1 inhibitors

The evasion from apoptosis is one of the main mechanisms contributing to tumor cell proliferation and survival and to chemoresistance [38]. B-cell lymphoma 2 (BCL-2) is a family of 18 proteins regulating the intrinsic apoptotic pathway, and is divided in anti-apoptotic proteins (such as BCL-2 and MCL-1), mediators of apoptosis (BAX and BAK) and proapoptotic proteins that inhibit the anti-apoptotic proteins and activate the mediators in case of cellular stress. Venetoclax is a selective orally administered inhibitor of the anti-apoptotic BCL-2 protein currently approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) and newly diagnosed acute myeloid leukemia. In preclinical models, venetoclax induced MM cell killing, especially in cells harboring t(11;14), and enhanced bortezomib activity [39,40]. Moreover, dexamethasone increased the expression of BCL-2, enhancing venetoclax activity [41]. These results prompted the investigation in clinical trials. Venetoclax demonstrated high efficacy in phase I trials as single agent (ORR 21%; 40% in t(11;14)-positive patients) and in combination with Vd (ORR among all enrolled patients 67%, with 43% ≥VGPR). The drug showed a favorable toxicity profile, with main G3-4 toxicities being hematologic (thrombocytopenia 26-29%, neutropenia 14-21%) [42,43]. The triplet venetoclax-Vd is being compared to Vd in the phase III randomized trial BELLINI, and preliminary results confirmed its efficacy (median PFS 22.9 vs. 11.4 months, HR 0.58), especially in t(11;14)-positive patients (median PFS NR vs. 9.3 months, HR=0.095)[44]. Although median OS was not reached in either arm, the addition of venetoclax to Vd resulted in a higher rate of deaths, as compared to placebo (HR for OS 1.47). The main causes of death were progression and
toxicity, particularly in terms of infections. Subgroup analyses confirmed this trend in
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t(11;14)-negative patients (HR for OS 1.54), but showed a positive trend in OS for t(11;14)- positive patients in the experimental arm (HR for OS 0.65), likely due to the lower risk of progression and related death. According to these findings, in 2019 the Food and Drug Administration (FDA) put on hold venetoclax-based clinical studies. Currently, the hold has been released only for venetoclax-based trials for t(11;14)-positive patients. Other venetoclax-containing regimens were evaluated in phase I/II trials. A phase II trial explored venetoclax-Kd in RRMM patients treated with 1-3 prior lines of therapy. ORR was 78%, with 56% ≥VGPR, while in t(11;14)-positive patients ORR was 100% with 88% ≥VGPR. Similar responses were observed in PI-refractory and double-refractory patients. Main G3-4 AEs were neutropenia (14%) and hypertension (12%) [45]. Another phase I/II trial is evaluating venetoclax with daratumumab-dexamethasone with or without bortezomib in RRMM patients. The preliminary efficacy is very encouraging, with 96% of t(11;14)-positive patients achieving ≥VGPR. These combinations appear safe, with main G3-4 AEs being, so far, neutropenia (13%) and insomnia (17%). Only the part of the trial on t(11;14)-positive patients is ongoing [46].
Besides BCL-2, another interesting target is the anti-apoptotic protein MCL-1, which is over- expressed in MM cells. Selective MCL-1 inhibitors showed encouraging preclinical activity in MM, particularly in combination with venetoclax [47]. Preliminary phase I/II trials with these agents have recently started and results are eagerly awaited.
3.2 Targeting BTK: ibrutinib

Ibrutinib is a selective inhibitor of Bruton’s Tyrosine Kinase (BTK), an enzyme that plays a central role in activating cellular pathways that promote B-cell proliferation and survival. Ibrutinib is orally administered and currently approved for the treatment of CLL, Waldenström macroglobulinemia (WM), relapsed mantle cell lymphoma and marginal zone lymphoma. BTK is expressed in 85% of MM cells and its activation contributes to sustaining MM cell growth and survival [48]. In preclinical models, ibrutinib inhibited MM cell growth by blocking the NF-kB pathway, thus resulting in the down-regulation of anti-apoptotic signaling. Ibrutinib enhanced the cytotoxic activity of bortezomib and, to less extent, lenalidomide, and restored bortezomib activity in bortezomib-resistant clones [49,50].

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Ibrutinib was initially tested as monotherapy or in combination with dexamethasone in heavily pretreated patients. Good tolerability but minimal activity were observed (ORR 5%) and median PFS was 4.6 months [51].
Ibrutinib was subsequently evaluated in combination with Vd in RRMM patients; the trial was interrupted early due to high toxicity, particularly in terms of infections (G≥3 43%). Moreover, toxic deaths occurred in 15% of patients and were mostly caused by infections (11%) [52]. Likely, this combination will not be evaluated further, given the safety concerns and an efficacy profile comparable to that of Vd alone [53,54]. More interesting results were obtained with ibrutinib-Kd in RRMM patients. At the MTD, ORR was 71% with 26% ≥VGPR, and median PFS and OS were 7.4 and 36 months, respectively. Efficacy was also observed in high-risk patients, with an ORR of 67% and a median PFS of 7.7 months. Key toxicities were thrombocytopenia (G≥3 26%), anemia (G≥3 17%), hypertension (19%), fatigue (G≥3 12%) and diarrhea (G≥3 10%) [55]. Limited evidence about the combination with IMDs suggested no significant efficacy of ibrutinib-Rd [56].
3.3 Targeting KSP: filanesib

Filanesib is a selective inhibitor of kinase spindle proteins (KSPs). KSPs mediate the separation of centrosomes during mitosis and are highly expressed in malignant cells with elevated proliferation index, like MM cells [57]. KSP blockage by filanesib induces cycle cell arrest and apoptosis through depletion of the anti-apoptotic protein MCL-1 [58]. In preclinical models, MM cells were particularly sensitive to filanesib, since their survival is strictly dependent on MCL-1 expression [59].
Filanesib was initially evaluated as monotherapy or in combination with dexamethasone in heavily pretreated patients. ORR was, respectively, 16% and 15% for patients receiving filanesib alone or filanesib-dexamethasone, with a median PFS of 1.6 and 2.8 months. At the MTD, the most common G3-4 toxicities were hematologic (49% neutropenia and thrombocytopenia, 44% anemia) [60]. Preclinical data showed that the activity of filanesib was impaired by high levels of acute phase reactant alpha 1-acid glycoprotein (AAG) [61]. AAG levels were therefore evaluated as biomarkers to predict filanesib efficacy in MM patients, showing that all patients achieving objective responses had AAG levels ≤110 mg/dL. Filanesib-Vd was evaluated in 55 RRMM patients: ORR was 20%, median duration of response
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was 14.1 months and patients with AAG levels ≤110 mg/dL tended to remain on study longer [62]. Filanesib was also evaluated in combination with Kd in RRMM patients: Median PFS and OS for all patients were 4.8 months and 24.9 months, respectively [63]. In vitro and in vivo preclinical models suggested a promising synergistic activity of filanesib-Pd [64] and a phase Ib/II trial with this triplet is being conducted on lenalidomide-refractory (94%)/intolerant patients. ORR was 65% with 12% ≥VGPR, and median PFS was 7 months, showing the greatest efficacy among the filanesib-containing combinations evaluated so far. Main G3-4 toxicities were hematologic (mainly neutropenia 60%) [65]. The introduction of new highly effective molecules, such as mAbs, has currently limited the further development of filanesib. Nevertheless, the combination of this agent with IMDs could be of future interest, particularly in selected patients with low AAG levels.
3.4 Targeting export proteins: selinexor and eltanexor

Export proteins like exportin 1 (XPO-1) regulate nuclear-cytoplasmic trafficking and are essential in maintaining cell homeostasis and survival. XPO-1 is overexpressed in several cancer cells, including MM, leading to cell cycle deregulation and evasion of apoptosis [66]. In preclinical studies, XPO-1 inhibitors showed significant anti-myeloma activity [67,68]. Selinexor is a first-generation selective oral inhibitor of XPO-1 that, in 2019, has received accelerated approval by FDA in combination with dexamethasone for the treatment of MM patients who already received ≥4 previous lines of therapy and are penta-refractory (refractory to at least 2 IMDs, 2 PIs and 1 anti-CD38 mAb). The approval was granted following the results of the phase II STORM trial on heavily pretreated patients (median prior lines: 7), of whom 96% were refractory to carfilzomib, pomalidomide and daratumumab. ORR was 26% and median PFS and OS were 3.7 and 8.6 months, respectively. Main G3-4 AEs were thrombocytopenia (59%), anemia (44%), hyponatremia (22%) and neutropenia (21%) [69]. Early-phase trials are showing promising results combining selinexor with several backbone treatments. Patients treated with the triplet selinexor-Vd achieved an ORR of 63% and a median PFS of 9 months, showing activity also in PI-refractory patients (ORR 43%, median PFS 6 months) [70]. Selinexor-Pd showed an ORR of 56% and a median PFS of 12.2 months in lenalidomide-refractory patients; these results compared favorably to those observed with Pd alone. The triplet showed activity also in pomalidomide-refractory patients (ORR 30%,
median PFS 5.6 months) [71]. Following these results, a phase III trial evaluating the triplet
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selinexor-Vd is ongoing (BOSTON trial, NCT0311056) and another trial evaluating selinexor- Pd is under development. Also selinexor in combination with Kd and with daratumumab showed encouraging preliminary results (ORR 71% and 76%, respectively), which compared favorably with those of Kd and daratumumab monotherapy in heavily pretreated patients [72,73]. Despite these promising results, concerns arose about selinexor-related toxicity that might prevent its continuous administration in heavily pretreated patients, who are generally fragile. Indeed, a recent meta-analysis on patients receiving selinexor in clinical trials reported a high incidence of nausea (68%), decrease in appetite (53%), weight loss (47%) diarrhea (41%) and vomiting (37%). These AEs were mostly limited to G1-2, with G≥3 AEs occurring in 5-7% of patients, but resulted in dose reductions and discontinuations; hyponatremia occurred in 32% of patients, with G≥3 in 19%; the main hematologic G3-4 AE was thrombocytopenia (54%) [74,75]. In preliminary studies, the second-generation selective XPO-1 inhibitor eltanexor demonstrated improved tolerability [76].
3.5 Targeting the cell cycle: dinaciclib

Dinaciclib is a selective inhibitor of cyclin-dependent kinases (CDK) 1/2/5/9, a family of proteins involved in the regulation of the cell cycle and in DNA repair. In MM, CDK activity is often dysregulated, and loss of CDK inhibitors has been demonstrated in MM cells. In particular, the inhibition of CDK5 enhances MM cell sensitivity to PIs, making this mechanism of action a target of interest [77]. Dinaciclib was initially tested as monotherapy in a phase I/II trial on RRMM patients. ORR was modest (11%) and median PFS and OS were 3.5 and 18.8 months, respectively. Main toxicities were hematologic, gastrointestinal (nausea and diarrhea) and fatigue, although G3-4 AEs were rare, with the exception of neutropenia [78]. A phase I trial with dinaciclib-Vd is currently ongoing (NCT01711528).
3.6 Targeting JAK: ruxolitinib

The activation of the Janus tyrosine kinase (JAK) pathway leads to the activation of transcriptional factors involved in cell proliferation and survival. Ruxolitinib is an oral inhibitor of JAK 1 and 2 and is currently approved for the treatment of myelofibrosis, polycythemia vera and graft-versus-host disease. Preclinical models showed that JAK inhibition with ruxolitinib induced apoptosis in MM cells [79,80]. Little clinical evidence is
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available about safety and efficacy of ruxolitinib in MM patients. Since preclinical models suggested that ruxolitinib could restore sensitivity to lenalidomide, a phase I trial with the triplet ruxolitinib-lenalidomide-methylprednisolone was conducted in RRMM patients (median prior lines: 6) who had already received both lenalidomide and a PI. The ORR was 37% with 13% ≥VGPR, and median PFS was 4 months. This fully oral novel combination was well tolerated, with reversible G≥3 hematologic AEs (neutropenia 12%, anemia 16%), thus allowing a further evaluation [81,82]. A phase I/II trial evaluating the combination of ruxolitinib-carfilzomib-dexamethasone in carfilzomib-refractory RRMM patients is ongoing (NCT03773107) [83].
3.7 Targeting G-protein-coupled receptors: imipridone ONC201

Imipridones are a novel class of molecule targeting G-protein-coupled receptors (GPCRs), which are involved in intracellular signaling. ONC201 is the first agent of this class under clinical development and targets a specific GPCR called DRD2. In MM cell lines, ONC201 induced p53-independent apoptosis associated with activation of the integrated stress response (ISR) pathway [84,85]. ONC201 was also active in MM cell lines resistant to bortezomib, carfilzomib and dexamethasone [86]. These results provide a strong rationale for clinical evaluation. Early-phase trials exploring the activity of ONC201 monotherapy (NCT02609230) or its combination with ixazomib-dexamethasone (NCT03492138) are ongoing.
3.8 Targeting histone deacetylase: ricolinostat

Histone deacetylases (HDACs) are a class of enzymes that modulate gene expression through epigenetic mechanisms. Their activity is often dysregulated in MM cells, leading to the over- expression of genes that promote cell proliferation and survival. HDAC inhibitors (HDACi) induce cell cycle arrest and apoptosis [87]. The first HDACi evaluated in MM, vorinostat, showed low activity and significant toxicity and further clinical development was consequently interrupted. Panobinostat showed greater efficacy in MM patients and was approved by the European Medicines Agency (EMA) and the FDA in 2015 for the treatment or RRMM, following the results of the phase III PANORAMA trial comparing the triplet panobinostat-VD to Vd [53]. However, safety concerns (particularly in terms of severe
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gastrointestinal toxicity and arrythmias) currently limit its use in clinical practice. In order to improve tolerability, ricolinostat, a selective HDACi directed against HDAC6, has been recently evaluated in MM. Single-agent activity was disappointing, whereas preliminary data of ricolinostat in combination with either lenalidomide or bortezomib showed acceptable efficacy (ORR 55% and 37%, respectively) and improved tolerability [88,89]. Another selective HDACi similar to ricolinostat, AC-241, is under evaluation in combination with Pd. Preliminary data reported an ORR of 50% [90]. Since confirmatory studies are needed to assess if these selective HDACi could be safer than panobinostat, their future role in the clinical scenario currently remains uncertain.
4. Immunotherapy: new compounds
Results of the main phase I/II clinical trials with immunotherapy agents on RRMM patients are summarized in Table 2; main mechanisms of action are shown in Figure 2.

4.1 Novel naked monoclonal antibodies

CD38 is a transmembrane protein with an ectoenzymatic activity [91,92] that plays a role in calcium homeostasis and cell signaling. The high expression of CD38 on MM cell surface made it an appealing target for drug development. Anti-CD38 mAbs daratumumab and isatuximab showed impressive results in RRMM, particularly in combination with IMDs or PIs. Recently, daratumumab has also been approved as upfront treatment for both transplant-eligible and – ineligible patients [93].
MOR202 is an IgG1 anti-CD38 mAb investigated in early-phase studies. Similarly, with other mAbs, it induces cell death through activation of Fc gamma receptors on immune cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell- mediated phagocytosis (ADCP). It seems to be associated with lower rates of infusion-related reactions (IRRs), which represent the most common AEs related to isatuximab and daratumumab. This could be due to a lower complement-dependent cytotoxicity (CDC), a feature of MOR202 observed in vitro [94]. In preclinical studies, MOR202 showed a synergistic effect with lenalidomide in modulating the immune microenvironment in MM [95]. MOR202 was evaluated in a phase I/IIa trial for RRMM patients [96,97], in combination
with dexamethasone, Rd or Pd. ORR was 28% in combination with dexamethasone, 65% in
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the Rd group and 48% in the Pd group. Median PFS was 8.4 months with MOR202- dexamethasone, NR with MOR202-Rd and 17.5 months with MOR202-Pd. IRRs were reported in 5-11% of subjects and were all limited to G1-2. Altogether, these results revealed a good tolerability of MOR202 and a promising efficacy in combination with IMDs. A randomized phase III trial comparing MOR202-Rd to Rd is ongoing.
TAK-079 is an IgG1-lambda anti-CD38 mAb. The main advantages of this novel compound are the subcutaneous administration route and the affinity to high-density CD38 targets that might reduce its binding to red blood cells and platelets. Thirty-four RRMM patients were treated with TAK-079 in a preliminary phase I/IIa study; 21% of them had already been exposed to anti-CD38 mAbs. TAK-079 monotherapy was well tolerated, with no dose-limiting toxicity (DLT), and MTD was not found. At the doses of 600 and 300 mg, no IRRs were reported. The efficacy was promising, with an ORR of 56% and 33% in the 300 mg and 600 mg cohorts, respectively. PFS was 3.7 months in the 300 mg dose cohort [98].
Novel targets for mAbs are currently under investigation. B-Cell maturation antigen (BCMA) is a cellular membrane glycoprotein with non-tyrosine kinase receptor activities from the tumor necrosis factor (TNF) receptor superfamily; it is highly expressed in plasma cells and in MM cells, and only in a subset of B cells [99,100]. BCMA was evaluated as a potential target in MM
[101] and two of its ligands were identified: a proliferation-inducing ligand (APRIL) and a B- cell activating factor (BAFF or BLyS). APRIL seems to be more plasma cell-specific and plays a role in paracrine stimulation of BCMA by MM cells [102]. In preclinical studies, the inhibition of APRIL-BCMA interaction through anti-APRIL mAb induced MM cell death and reduced cell adhesion and migration blocking NF-kB signaling. [103]. On this basis, the anti-APRIL mAb BION-1301 was recently investigated in a phase I/II study for the treatment of RRMM. Up to now, 5 of the 14 evaluable patients have achieved a SD, while no objective response has been observed [104]. Given its lack of efficacy, this agent likely will not be investigated further.
The CXCR4/CXCL12 axis is an interesting target for the treatment of MM. CXCR4 is a chemokine receptor and plays a central role in cancer cell proliferation, migration and dissemination inside and outside the bone marrow [105]. Preclinical data showed that CXCR4 was hyperexpressed in MM cells, showing evidence of a possible role of CXCR4 inhibition in the treatment of MM [106,107]. Ulocuplumab is a human IgG4 mAb that binds to CXCR4. A phase Ib/II study was performed with ulocuplumab combined with either Rd (cohort A) or Vd
(cohort B). RRMM patients with 3 median prior lines were enrolled. Most common G>3 AEs
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were neutropenia (30% in cohort A, 6.3% in cohort B) and thrombocytopenia (16% in cohort A, 18% in cohort B). ORR was 55% in cohort A (with 16% of patients achieving a complete response (CR) or better) and 25% in cohort B. Median PFS was 22.3 months in cohort A and
9.6 months in cohort B. According to its possible role in the genesis of extramedullary dissemination of MM, inhibition of CXCR4 could be important for the treatment of extramedullary MM.

 

4.2 Antibody-drug conjugates (ADCs)

ADCs combine a mAb with a cytotoxic agent through a molecular linker. Their biological rationale is to deliver and lead the internalization of a cytotoxic drug into specific cells that express an antigen targeted by the mAb. This is a well-established strategy and there are several ADCs used in clinical practice such as brentuximab vedotin for relapsed/refractory Hodgkin’s lymphoma [108,109] and CD30-positive lymphomas [110], and inotuzumab ozogamicin for relapsed/refractory acute lymphoblastic leukemia (ALL) [111]. One of the most important advantages in ADC mechanism of action is that the cytotoxic activity is delivered only to cells targeted by mAbs, thus sparing normal cells from toxicity. Cytotoxic agents combined to a mAb are usually extremely active toxins that cannot be used systemically due to their toxicities. Their activity could rely on DNA damage (calicheamicins) or on the interference with cell cycle by inhibiting microtubule formation (maytansinoid derivatives: emtansine, mertansine, soravtansine and ravtansine; auristatin derivatives: monomethyl auristatin E [MMAE, vedotin] and monomethyl auristatin F [MMAF, mafodotin]) [112]. The crucial point in developing ADCs is to find an antigen selectively expressed in tumor cells.
Belantamab mafodotin is the first anti-BCMA ADC conjugated with the toxic anti-microtubule agent MMAF. In addition to its activity due to MMAF, belantamab mafodotin also induces immunogenic cell death by ADCP and ADCC [100,113]. The first in-human single-agent activity was studied in the phase I/II DREAMM-1 trial. Overall, 73 patients were enrolled, the majority of whom were heavily pretreated. Main toxicities were ophthalmologic and hematologic (any-grade thrombocytopenia 61%). Ocular toxicity consisted mainly of blurred vision (52%) and keratitis (9%) and was likely related to MMAF, also considering that similar
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AEs were reported with other ADCs with MMAF [114]. G3-4 AEs were mostly hematologic and IRRs occurred only in 6% of patients. The efficacy report was encouraging, with an ORR of 60%, including 5 patients achieving at least a CR and 14 a VGPR, and a median PFS of 12 months [115,116]. The phase II DREAMM-2 study evaluated 2 drug doses (2.5 mg/kg and 3.4 mg/kg) in patients relapsed or refractory to PIs, IMDs and anti-CD38. A specific attention was put on the management of ocular toxicity, the prevention through periodic ocular examination by ophthalmologists and the administration of steroid eye drops, artificial tears and cooling eye masks. The most frequent ocular-referred symptoms were blurred vision and dry eye. In the two cohorts, 36% and 28% of patients with ocular AEs recovered. A longer follow-up is needed to understand the long-term evolution of ocular toxicity. G≥3 AEs were keratopathy (27% and 21% in the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively), thrombocytopenia
(20% and 33%), and anemia (20% and 25%). Dose reductions were frequent (29% and 41%) and mainly due to ocular toxicity. IRRs occurred in 15% and 18% of patients and were mostly G1-2 and limited to the first infusion.
Regarding efficacy, ORR was 31% in the 2.5 mg/kg cohort and 34% in the 3.4 mg/kg cohort, with 19% and 20% ≥VGPR, respectively. Median PFS was 2.9 months and 4.9 months, respectively. Given the similar efficacy and the more favorable safety profile, 2.5 mg/kg was the recommended dose for further study [117]. These encouraging results paved the way for the evaluation of belantamab mafodotin in comparison and in combination with several backbone MM agents. The DREAMM-3 (NCT04162210) trial will compare belantamab mafodotin to Pd; the DREAMM-7 (NCT04246047) belantamab mafodotin-Vd to daratumumab-Vd in RRMM patients; the NCT04091126 belantamab mafodotin-VRd to VRd in transplant-ineligible NDMM patients. At the beginning of 2020, the FDA put belantamab mafodotin into the list of drugs that have been granted priority review to receive approval.
CD138, also known as syndecan-1, is a surface cell receptor expressed in MM cells that functions as adhesion molecule and is commonly used as a diagnostic marker [118] to identify MM cells. Indatuximab ravtansine (IR or BT-062) is a CD138 mAb linked to anti-microtubule cytotoxic compound maytansinoid DM4. In a preliminary study, IR monotherapy was tested in heavily pretreated RRMM patients. Although the safety profile was good, only 6% of patients showed an objective response [119]. In order to increase efficacy, IR was then studied in a phase I/IIa trial in combination with Rd or Pd. The combination IR-Rd showed an ORR of 77%

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and a median PFS of 16.4 months. Subjects receiving IR-Pd had a similar ORR of 79% and a median PFS NR (follow-up: 7 months) [120].
CD56 is a neural cell adhesion molecule (NCAM), a membrane glycoprotein of the immunoglobulin superfamily [121]. Normally, it is expressed in natural killer cells and absent in plasma cells, although it could be present in 60-80% of MM cells [122,123]. Lorvotuzumab mertansine (LM, IMGN901) is an anti-CD56 mAb associated with the microtubule inhibitor mertansine, which causes cell death by blocking mitosis. In a phase I trial, it was evaluated as monotherapy in 37 RRMM patients screened for CD56 positivity. The safety profile was acceptable, with peripheral neuropathy being the most common AE (G3-4 5.3%) leading to discontinuation. Regarding efficacy, 6% of patients reached a PR and 43% a SD; median PFS was 6.5 months [124]. Lorvotuzumab mertansine is also under evaluation in combination with Rd; early results of this phase I study revealed an ORR of 56% [125].
Fc receptor-homolog 5 (FcRH5) has been recently discovered as a potential target due to its high expression on MM cells. FcRH5 is a surface receptor expressed only on B cells and plasma cells, with a higher expression on MM cells [126–129]. The ADC DFRF4539A is based on the association of anti-FcRH5 mAb with MMAE. In a phase I trial, it showed a modest efficacy as monotherapy (ORR of 8%) in 39 patients [130].
The therapeutic approach based on the combination of a compound that is toxic for MM cells with a naked mAb is not limited to ADC. Indeed, TAK-573 is an anti-CD38 mAb that is fused to an attenuated form of human interferon alpha (IFN-a). This agent showed efficacy in preclinical models and a phase I/IIa trial (NCT03215030) is ongoing [131].

4.3. Bispecific T-cell engagers (BTEs)

BTEs are antibody constructs that link immune cells and cancer cells, thus creating a bridge known as “immunological synapse”. These compounds activate engaged T cells which release cytokines that recruit polyclonal T cells for tumor killing. Once the T cells are close to the tumor, they can kill the tumor cells [132]. Blinatumomab was the first BTE to be approved for relapsed/refractory ALL [133]. The most important AEs related to this novel therapeutic strategy were cytokine release syndrome (CRS) and neurological toxicities [134].
The first BTEs developed for MM had BCMA as target [135]. In January 2020, results of a phase I study on 42 RRMM patients treated with BCMA BTE AMG 420 have been published
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[136]. Patients received AMG 420 up to 10 cycles, with a schedule of 4-week infusions in 6- week cycles and dose escalations. Sixteen patients developed CRS (only 1 G3). Two of the 3 patients treated with 800 mg/d experienced DLTs (1 G3 CRS and 1 G3 polyneuropathy), and therefore this dose was defined as MTD. Discontinuations were mainly due to PD (60%) and 17% of them were due to AEs. Significant efficacy was observed with an ORR of 70%, including 5 patients achieving a ≥CR with minimal residual disease (MRD) negativity. Median response duration was 9 months. Taken together, these results appear promising and a phase Ib study with subcutaneous AMG 420 is ongoing. AMG-701, another anti-BCMA BTE, is under study in the first phase I trial [137] and has the advantage of a longer half-life, allowing a shorter administration.
CC-93269 is an asymmetric 2-arm humanized IgG T-cell engager that binds with 2 parts to BCMA and CD3 in a 2+1 format [138,139]. In a phase I trial, 19 heavily pretreated MM patients received this drug. CRS, mostly of G1-2, was experienced by 76% of patients. The ORR was 43%, with 17% of patients achieving ≥CR with MRD negativity. In a group receiving 10 mg (maximum dose), the ORR was 88%, with 44% of patients achieving ≥CR. Other anti- BCMA/CD3 BTEs (PF-3135 and REGN5458) are under preliminary evaluation in phase I trials [140,141]. The FCRH5/CD3 BTE known as BFCR4350A has been evaluated in the preclinical setting, showing high efficacy and long half-life [129]; a Phase I trial is active (NCT03275103).

5. Conclusion
In conclusion, this review describes several new drugs for MM treatment, and some of them appear extremely promising. However, all that glitters is not gold: it is essential to identify the agents that could make a difference in the disease course and obtain a worthy evaluation in larger phase III trials.
6. Expert opinion
To date, there is no evidence of a curative approach for MM patients, even combining available drugs in triplets and quadruplets [142]. We need to identify effective therapies for patients who relapsed or became refractory after treatment with novel agents. Indeed, patients refractory to anti-CD38 mAbs experience an estimated PFS of 3-5 months and an OS

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of 6-15 months [143–145]. In this perspective, some very promising compounds have been described in this article. The new-generation IMD CC-220 showed responses in about one- third of MM patients already exposed to PIs, IMDs and daratumumab [24]. Selinexor- dexamethasone showed a similar ORR in heavily pretreated patients [69]. These agents likely hold an even greater potential when used in combination therapies in earlier lines. Finding the best partner for each drug is challenging and requires the identification of the possible synergies and toxicities of each agent. In this view, the combinations of the KSP inhibitor filanesib with IMDs and of selinexor with PIs appear promising. The expansion of the treatment armamentarium for MM implies that the identification of the best sequence for the administration of new molecules becomes crucial to limit the progressive decrease in effectiveness observed after each subsequent line of therapy.
Immunotherapy is the rising star in MM treatment. Among naked mAbs, daratumumab and isatuximab have safety and efficacy profiles that are difficult to improve. Reasons for developing new anti-CD38 mAbs are the identification of molecules that may be effective in daratumumab-resistant/refractory patients or that induce less IRRs and have more convenient schedules of administration. MOR202 showed promising efficacy in association with Rd and Pd in RRMM patients and its advantages are the lower IRR rate and the shorter infusion time. Whether MOR202 and TAK-79 could be active in patients relapsing after a daratumumab-based therapy remains undetermined.
Among ADCs, the anti-BCMA belantamab mafodotin is in the spotlight and proved to be active in daratumumab-refractory patients. Nonetheless, ocular toxicity could be an issue for its long-term use, since its full reversibility remains uncertain. Aside from belantamab mafodotin, the other ADCs evaluated for the treatment of MM showed dismal results and are not likely to be investigated further. BCMA is also the target for active immunotherapy, with anti-BCMA-CD3 BTEs seeming to induce deep responses also in heavily pretreated patients, who in some cases achieved MRD negativity. Moreover, CRS and CNS toxicities appear less burdensome than those observed with CAR-T therapy, although no direct comparisons are available [146]. On the other hand, their usage has some limitations, such as the inconvenient administration schedules, with continuous infusions that cannot be provided by all oncology centers. New agents with more convenient pharmacokinetics and formulations are under evaluation.

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An open question is, what will be the role of new molecules and immunotherapeutic approaches in the era of cellular therapies? CAR-T cell therapy showed encouraging results in RRMM patients, and efforts to optimize this strategy are being made worldwide. However, it requires careful patient selection and high costs, and patients relapse even after achieving deep responses [147]. Interestingly, selinexor induced responses in patients relapsing after CAR-T cell therapy [148]. To date, cellular therapy cannot completely substitute the development of new molecules.
Aside from the management of RR disease, new drugs are needed to achieve deeper responses and sustained remissions during first-line therapy [149,150]. The achievement of MRD negativity has been strongly linked to longer PFS and OS [149,150]. However, even with the best combinations available for first-line therapy, there will be a substantial group of patients not reaching MRD negativity [151–154]. In these patients, an approach based on targets not covered by conventional combinations (such as BCMA, for instance using belantamab or BTEs during maintenance) could lead to higher MRD-negativity rates, with fewer toxicities in NDMM than in RRMM patients. This MRD-driven approach could be crucial for the achievement of longer survival rates [142].
In the context of MM, personalized therapy and risk-adapted strategies have not been as widely adopted as in other oncology fields. Venetoclax could pave the way for target therapy in MM, given its outstanding efficacy in patients carrying t(11;14) [42,43]. Indeed, despite some toxicity concerns, its benefits seem to overtake risks in this subset of patients. Another challenge is the identification of biomarkers that could predict response to treatment, as is the case of low AAG levels predicting high efficacy with filanesib.
In the history of MM, ‘unity is strength’ and combining different drugs is the key to success. Regulatory trials will determine whether the new drugs discussed in this article will be safely and effectively added to backbone treatments.

Authorship contributions
All the authors conceived and designed the work that led to the submission, collected the data and interpreted the results, drafted the first version and revised the final version of the manuscript, approved the final version of the manuscript, and agreed to be accountable for all
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aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding
This paper was not funded.
Declaration of interest
M Boccadoro has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol- Myers Squibb, and AbbVie; has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma. S Bringhen has received honoraria from Celgene, Amgen and Janssen, and Bristol-Myers Squibb; has served on the advisory boards for Celgene, Amgen, Janssen, and Karyopharm; has received consultancy fees from Janssen and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
One reviewer has participated in CC220 trials involving most of the cited drugs in this article. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose
References
Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers

[1] Myeloma – Cancer Stat Facts [Internet]. Natl. Cancer Inst. – Surveillance, Epidemiol. End Results Progr. [cited 2018 Dec 12]. Available from: https://seer.cancer.gov/statfacts/html/mulmy.html.
[2] Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood [Internet]. 2008 [cited 2018 Feb 9];111:2516– 2520. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17975015.
[3] Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia

22

[Internet]. 2014 [cited 2017 Sep 6];28:1122–1128. Available from: http://www.nature.com/doifinder/10.1038/leu.2013.313.
[4] Bonello F, Mina R, Boccadoro M, et al. Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma. Cancers (Basel). [Internet]. 2019 [cited 2020 Feb 3];12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31861548.
[5] Nunes AT, Annunziata CM. Proteasome inhibitors: structure and function. Semin. Oncol.
W.B. Saunders; 2017. p. 377–380.
[6] Gandolfi S, Laubach JP, Hideshima T, et al. The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev. 2017;36:561–584.
[7] Zhou HJ, Aujay MA, Bennett MK, et al. Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J. Med. Chem. 2009;52:3028–3038.
[8] Chauhan D, Singh A V., Aujay M, et al. A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood. 2010;116:4906–4915.
[9] Ghobrial IM, Vij R, Siegel D, et al. A phase Ib/II study of oprozomib in patients with advanced multiple myeloma and Waldenstrom € macroglobulinemia. Clin. Cancer Res. 2019;25:4907–4916.
[10] Hari P, Paba-Prada CE, Voorhees PM, et al. Efficacy and safety results from a phase 1b/2, multicenter, open-label study of oprozomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Leuk. Res. 2019;83.
[11] Shah J, Usmani S, Stadtmauer EA, et al. Oprozomib, pomalidomide, and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma. Clin. Lymphoma, Myeloma Leuk. 2019;19:570-578.e1.
[12] Hari P, Matous J V., Voorhees PM, et al. Oprozomib in patients with newly diagnosed multiple myeloma. Blood Cancer J. Nature Publishing Group; 2019.
[13] Chauhan D, Singh A V., Ciccarelli B, et al. Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood. 2010;115:834–845.
[14] Di K, Lloyd GK, Abraham V, et al. Marizomib activity as a single agent in malignant gliomas: Ability to cross the blood-brain barrier. Neuro. Oncol. [Internet]. 2016 [cited

23

2020 Mar 19];18:840–848. Available from: https://pubmed.ncbi.nlm.nih.gov/26681765/.
[15] Badros A, Singh Z, Dhakal B, et al. Marizomib for central nervous system-multiple myeloma. Br. J. Haematol. 2017;177:221–225.
[16] Haslett PAJ, Corral LG, Albert M, et al. Thalidomide costimulates primary human t lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J. Exp. Med. 1998;187:1885–1892.
[17] Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of ikaros proteins. Science (80-. ). 2014;343:305–309.
[18] Krönke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science (80-. ). 2014;343:301–305.
[19] LeBlanc R, Hideshima T, Catley LP, et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood. 2004;103:1787–1790.
[20] Henry JY, Labarthe MC, Meyer B, et al. Enhanced cross-priming of naive CD8+ T cells by dendritic cells treated by the IMiDs® immunomodulatory compounds lenalidomide and pomalidomide. Immunology. 2013;139:377–385.
[21] Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science (80-. ). 2010;327:1345–1350.
[22] Bjorklund CC, Kang J, Amatangelo M, et al. Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN. Leukemia. Nature Publishing Group; 2019.
[23] Matyskiela ME, Zhang W, Man HW, et al. A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. J. Med. Chem. 2018;61:535–542.
[24] Lonial S, Van de Donk N, Popat R, et al. A Phase 1b/2a Study of the CELMoD Iberdomide (CC-220) in Combination With Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. Clin. Lymphoma Myeloma Leuk. 2019;19:e52-e53 [Abstract, IMWG 2019 Meeting].
[25] Hagner PR, Man HW, Fontanillo C, et al. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood. 2015;126:779–789.
[26] Rasco DW, Papadopoulos KP, Pourdehnad M, et al. A first-in-human study of novel cereblon modulator avadomide (CC-122) in advanced malignancies. Clin. Cancer Res.

24

2019;25:90–98.
[27] Lopez-Girona A, Havens CG, Lu G, et al. CC-92480 Is a Novel Cereblon E3 Ligase Modulator with Enhanced Tumoricidal and Immunomodulatory Activity Against Sensitive and Resistant Multiple Myeloma Cells. Blood. 2019;134:Abstract #1812 [ASH 2019 61st Meeting].
[28] Wickström M, Larsson R, Nygren P, et al. Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci. 2011. p. 501–508.
[29] Chauhan D, Ray A, Viktorsson K, et al. In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. Clin. Cancer Res. 2013;19:3019–3031.
[30] Ray A, Ravillah D, Das DS, et al. A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br. J. Haematol. 2016;174:397– 409.
[31] Wickström M, Haglund C, Lindman H, et al. The novel alkylating prodrug J1: Diagnosis directed activity profile ex vivo and combination analyses in vitro. Invest. New Drugs. 2008;26:195–204.
[32] Bringhen S, Voorhees PM, Plesner T, et al. Updated Progression-Free Survival (PFS) and Overall Survival (OS) with Melflufen and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Phase 2 Study O-12- M1. Blood. 2019;134:Abstract #1839 [ASH 2019 61st Meeting].
[33] Richardson PG, Bringhen S, Voorhees P, et al. Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, phase 1–2 study. Lancet Haematol. 2020;
[34] Mateos M-V, Oriol A, Larocca A, et al. Clinical Activity of Melflufen in Patients with Triple-Class Refractory Multiple Myeloma and Poor-Risk Features in an Updated Analysis of HORIZON (OP-106), a Phase 2 Study in Patients with Relapsed/Refractory Multiple Myeloma Refractory to Pomalidomide and/or Daratumumab. Blood. 2019;134:Abstract #1883 [ASH 2019 61st Meeting].
[35] Richardson PG, Mateos M-V, Rodríguez-Otero P, et al. Activity of Melflufen in RR MM Patients with Extramedullary Disease in the Phase 2 HORIZON Study (OP-106): Promising Results in a High-Risk Population. 17th International Myeloma Workshop [IMW] Abstract Book. 2019. p. 545-546 [Abstract #OAB-86].

25

[36] Schjesvold F, Robak P, Pour L, et al. OCEAN: A randomized Phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma. Futur. Oncol. 2020;16:631–641.
[37] Ocio EM, Efebera YA, Granell M, et al. ANCHOR (OP-104): Updated Efficacy and Safety from a Phase 1/2 Study of Melflufen and Dexamethasone Plus Bortezomib or Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Refractory to an IMiD or a Proteasome Inhibitor (PI). Blood. 2019;134:Abstract #3124 [ASH 2019 61st Meeting].
[38] Letai AG. Diagnosing and exploiting cancer’s addiction to blocks in apoptosis. Nat. Rev. Cancer. Nat Rev Cancer; 2008. p. 121–132.
[39] Bodet L, Gomez-Bougie P, Touzeau C, et al. ABT-737 is highly effective against molecular subgroups of multiple myeloma. Blood. 2011;118:3901–3910.
[40] Touzeau C, Dousset C, Le Gouill S, et al. The Bcl-2 specific BH3 mimetic ABT-199: A promising targeted therapy for t(11;14) multiple myeloma. Leukemia. Leukemia; 2014. p. 210–212.
[41] Matulis SM, Gupta VA, Nooka AK, et al. Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax. Leukemia. 2016;30:1086–1093.
[42] Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood [Internet]. 2017 [cited 2018 Jan 31];130:2401–2409. Available from: http://www.bloodjournal.org/lookup/doi/10.1182/blood-2017-06-788786.
[43] Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017;130:2392–2400.
[44] Moreau P, Harrison S, Cavo M, et al. Updated Analysis of Bellini, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. Blood. 2019;134:Abstract #1888 [ASH 2019 61st Meeting].
[45] Costa LJ, Stadtmauer EA, Morgan G, et al. Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. Blood. 2018;132:303–303.

26

[46] Bahlis N, Baz R, Harrison S, et al. First Analysis from a Phase 1/2 Study of Venetoclax in Combination with Daratumumab and Dexamethasone, +/- Bortezomib, in Patients with Relapsed/Refractory Multiple Myeloma. Blood. 2019;134:Abstract #925 [_ASH 2019 61st Meeting].
[47] Algarín EM, Díaz-Tejedor A, Mogollón P, et al. Preclinical evaluation of the simultaneous inhibition of MCL-1 and BCL-2 with the combination of S63845 and venetoclax in multiple myeloma. Haematologica. Ferrata Storti Foundation; 2020. p. E116–E120.
[48] Liu Y, Dong Y, Jiang QL, et al. Bruton’s tyrosine kinase: Potential target in human multiple myeloma. Leuk. Lymphoma. 2014;55:177–181.
[49] Rushworth SA, Bowles KM, Barrera LN, et al. BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-κB. Cell. Signal. 2013;25:106–112.
[50] Murray MY, Zaitseva L, Auger MJ, et al. Ibrutinib inhibits BTK-driven NF-κ B p65 activity to overcome bortezomib-resistance in multiple myeloma. Cell Cycle. 2015;14:2367– 2375.
[51] Richardson PG, Bensinger WI, Huff CA, et al. Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results. Br. J. Haematol. 2018;180:821–830.
[52] Hajek R, Pour L, Ozcan M, et al. A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Eur. J. Haematol. 2019;
[53] San-Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. [Internet]. 2014 [cited 2017 Jul 14];15:1195– 1206. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1470204514704401.
[54] Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016;375:754–766.
[55] Chari A, Cornell RF, Gasparetto C, et al. Final analysis of a phase 1/2b study of ibrutinib combined with carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma. Hematol. Oncol. 2020;

27

[56] Ailawadhi S, Paulus A, Alegria VR, et al. Phase I Trial of Ibrutinib, Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM). Blood. 2019;134:1912–1912.
[57] Slangy A, Lane HA, d’Hérin P, et al. Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell. 1995;83:1159–1169.
[58] Algarín EM, Hernández-García S, Garayoa M, et al. Filanesib for the treatment of multiple myeloma. Expert Opin. Investig. Drugs. 2020;29:5–14.
[59] Tunquist BJ, Woessner RD, Walker DH. Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520. Mol. Cancer Ther. 2010;9:2046–2056.
[60] Shah JJ, Kaufman JL, Zonder JA, et al. 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.
[61] Tunquist B, Brown K, Hingorani G, et al. Identification of Alpha 1-Acid Glycoprotein (AAG) As a Potential Patient Selection Biomarker for Improved Clinical Activity of the Novel KSP Inhibitor ARRY-520 in Relapsed and Refractory Multiple Myeloma (MM). Blood. 2012;120:1868–1868.
[62] Chari A, Htut M, Zonder JA, et al. A phase 1 dose-escalation study of filanesib plus bortezomib and dexamethasone in patients with recurrent/refractory multiple myeloma. Cancer. 2016;122:3327–3335.
[63] Lee HC, Shah JJ, Feng L, et al. A phase 1 study of filanesib, carfilzomib, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Blood Cancer J. Nature Publishing Group; 2019.
[64] Hernández-García S, San-Segundo L, González-Méndez L, et al. The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma. Haematologica. 2017;102:2113–2124.
[65] Ocio E, Motllo C, Rodriguez-Otero P, et al. Safety and Efficacy of Filanesib in Combination with Pomalidomide and Dexamethasone in Refractory MM Patients. Phase Ib/II Pomdefil Clinical Trial Conducted By the Spanish MM Group. Blood. 2017;130:Abstract #1873 [ASH 2017 59th Meeting].
[66] Hill R, Cautain B, De Pedro N, et al. Targeting nucleocytoplasmic transport in cancer

28

therapy. Oncotarget. Impact Journals LLC; 2014. p. 11–28.
[67] Schmidt J, Braggio E, Kortuem KM, et al. 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.
[68] Tai YT, Landesman Y, Acharya C, et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: Molecular mechanisms and therapeutic implications. Leukemia. 2014;28:155–165.
[69] Chari A, Vogl DT, Gavriatopoulou M, et al. Oral Selinexor–Dexamethasone for Triple- Class Refractory Multiple Myeloma. N. Engl. J. Med. [Internet]. 2019 [cited 2020 Mar 19];381:727–738. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1903455.
[70] Bahlis NJ, Sutherland H, White D, et al. Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma. Blood. 2018;132:2546–2554.
[71] Chen CI, Bahlis N, Gasparetto C, et al. Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma. Blood. 2019;134:Abstract #141 [ASH 2019 61st Meeting].
[72] Gasparetto C, Schiller GJ, Callander NS, et al. A Phase 1b/2 Study of Selinexor, Carfilzomib, and Dexamethasone (SKd) in Relapsed/ Refractory Multiple Myeloma (RRMM). Blood. 2019;134:Abstract #3157 [ASH 2019 61st Meeting].
[73] Gasparetto C, Lentzsch S, Schiller G, et al. A PHASE 1B STUDY USING THE COMBINATION OF SELINEXOR, DARATUMUMAB, AND DEXAMETHASOME IN MULTIPLE MYELOMA PATIENTS PREVIOUSLY EXPOSED TO PROTEASOME INHIBITORS AND IMMUNOMODULATORY DRUGS. HemaSphere. 2018;2(S1):606 [Abstract #PS1329, EHA 2018 Annual Congress].
[74] Gavriatopoulou M, Chari A, Chen C, et al. Integrated safety profile of selinexor in multiple myeloma: experience from 437 patients enrolled in clinical trials. Leukemia. 2020;[Ahead of print].
[75] Mikhael J, Noonan KR, Faiman B, et al. Consensus Recommendations for the Clinical Management of Patients With Multiple Myeloma Treated With Selinexor. Clin. Lymphoma, Myeloma Leuk. Elsevier Inc.; 2020.
[76] Cornell RF, Rossi AC, Baz R, et al. Eltanexor (KPT-8602), a Second-Generation Selective

29

Inhibitor of Nuclear Export (SINE) Compound, in Patients with Refractory Multiple Myeloma. Blood [Internet]. 2017 [cited 2020 Mar 19];130:Abstract #3134 [ASH 2017 59th Meeting]. Available from: https://doi.org/10.1182/blood.V130.Suppl_1.3134.3134.
[77] Zhu YX, Tiedemann R, Shi CX, et al. RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5. Blood. 2011;117:3847–3857.
[78] Kumar SK, LaPlant B, Chng WJ, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015;125:443–448.
[79] Chatterjee M, Stühmer T, Herrmann P, et al. Combined disruption of both the MEK/ERK and the IL-6R/STAT3 pathways is required to induce apoptosis of multiple myeloma cells in the presence of bone marrow stromal cells. Blood. 2004;104:3712–3721.
[80] Monaghan KA, Khong T, Burns CJ, et al. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia. 2011;25:1891–1899.
[81] Berenson JR, To J, Spektor TM, et al. A Phase 1 Trial of Ruxolitinib, Lenalidomide and Methylprednisolone for Patients with Relapsed/Refractory Multiple Myeloma (MM). Blood. 2019;134:Abstract #1903 [ASH 2019 61st Meeting].
[82] Berenson JR, To J, Spektor TM, et al. A Phase I Study of Ruxolitinib, Lenalidomide, and Steroids for Patients with Relapsed/Refractory Multiple Myeloma. Clin. Cancer Res. 2020;
[83] Atrash S, Robinson M, Bhutani M, et al. Phase I/II Study of Carfilzomib, Ruxolitinib and Low-Dose Dexamethasone for Carfilzomib-Refractory Multiple Myeloma (CarJak). Blood. 2019;134:Abstract #5570 [ASH 2019 61st Meeting].
[84] Tu Y sheng, He J, Liu H, et al. The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma. Neoplasia (United States). 2017;19:772–780.
[85] Prabhu V V., Talekar MK, Lulla AR, et al. Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies. Cell Cycle. 2018;17:468–478.
[86] Tu Y, He J, Liu H, et al. ONC201 Overcomes Chemotherapy Resistance By Upregulation

30

of Bim in Multiple Myeloma. Blood. 2016;128:Abstract #4476 [ASH 2016 58th Meeting].
[87] Richardson PG, Mitsiades CS, Laubach JP, et al. Preclinical data and early clinical experience supporting the use of histone deacetylase inhibitors in multiple myeloma. Leuk. Res. 2013. p. 829–837.
[88] Vogl DT, Raje N, Jagannath S, et al. 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.
[89] Yee AJ, Bensinger WI, Supko JG, et al. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol. 2016;17:1569–1578.
[90] Niesvizky R, Richardson PG, Yee AJ, et al. 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:Abstract #3307 [ASH 2016 58th Meeting].
[91] Deaglio S, Mehta K, Malavasi F. Human CD38: a (r)evolutionary story of enzymes and receptors. Leuk. Res. [Internet]. 2001 [cited 2017 Dec 14];25:1–12. Available from: http://www.sciencedirect.com/science/article/pii/S014521260000093X.
[92] Malavasi F, Deaglio S, Funaro A, et al. Evolution and Function of the ADP Ribosyl Cyclase/CD38 Gene Family in Physiology and Pathology. Physiol. Rev. [Internet]. 2008 [cited 2018 Sep 4];88:841–886. Available from: http://www.physiology.org/doi/10.1152/physrev.00035.2007.
[93] Bonello F, D’Agostino M, Moscvin M, et al. CD38 as an immunotherapeutic target in multiple myeloma. Expert Opin. Biol. Ther. [Internet]. 2018 [cited 2019 Apr 5];18:1209–1221. Available from: https://www.tandfonline.com/doi/full/10.1080/14712598.2018.1544240.
[94] Lammerts van Bueren J, Jakobs D, Kaldenhoven N, et al. Direct in Vitro Comparison of Daratumumab with Surrogate Analogs of CD38 Antibodies MOR03087, SAR650984 and Ab79. Blood. 2014;124:Abstract #3474 [ASH 2014 56th Meeting].
[95] Busch L, Mougiakakos D, Büttner-Herold M, et al. Lenalidomide enhances MOR202- dependent macrophage-mediated effector functions via the vitamin D pathway. Leukemia. 2018;32:2445–2458.

31

[96] Raab MS, Engelhardt M, Blank A, et al. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1–2a trial. Lancet Haematol. 2020;7:e381–e394.
[97] D’Agostino M, Mina R, Gay F. Anti-CD38 monoclonal antibodies in multiple myeloma: another cook in the kitchen? Lancet Haematol. 2020;7:e355–e357.
[98] Krishnan AY, Patel KK, Hari P, et al. Preliminary Results from a Phase 1b Study of TAK- 079, an Investigational Anti-CD38 Monoclonal Antibody (mAb) in Patients with Relapsed/ Refractory Multiple Myeloma (RRMM). Blood. 2019;134:Abstr. 140 [Updated results presented at ASH 2019].
[99] Claudio JO, Masih-Khan E, Tang H, et al. A molecular compendium of genes expressed in multiple myeloma. Blood. 2002;100:2175–2186.
[100] Tai YT, Mayes PA, Acharya C, et al. Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood. 2014;123:3128–3138.
[101] Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. [Internet]. 2013 [cited 2018 Feb 6];19:2048–2060. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23344265.
[102] Belnoue E, Pihlgren M, McGaha TL, et al. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood. 2008;111:2755–2764.
[103] Tai YT, Acharya C, An G, et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood. 2016;127:3225–3236.
[104] Bensinger W, Raptis A, Berenson JR, et al. Safety and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma. J. Clin. Oncol. [Internet]. 2019 [cited 2020 Mar 19];37:Abstract #8012 [ASCO 2019 Annual Meeting]. Available from: http://ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.8012.
[105] Domanska UM, Kruizinga RC, Nagengast WB, et al. A review on CXCR4/CXCL12 axis in oncology: No place to hide. Eur. J. Cancer. 2013;49:219–230.
[106] Alsayed Y, Ngo H, Runnels J, et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)- dependent migration and homing in multiple myeloma. Blood. 2007;109:2708–2717.
[107] Kuhne MR, Mulvey T, Belanger B, et al. BMS-936564/MDX-1338: A fully human anti- CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin. Cancer Res. 2013;19:357–366.
[108] Younes A, Gopal AK, Smith SE, et al. Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin’s Lymphoma. J. Clin. Oncol. [Internet]. 2012 [cited 2019 Oct 14];30:2183–2189. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22454421.
[109] Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N. Engl. J. Med. 2018;378:331–344.
[110] Prince HM, Kim YH, Horwitz S, et al. Brentuximab vedotin or physician’s choice in CD30- positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017;390:555–566.
[111] Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N. Engl. J. Med. [Internet]. 2016 [cited 2020 Mar 19];375:740–753. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1509277.
[112] Peters C, Brown S. Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Biosci. Rep. 2015;35:e00225–e00225.
[113] De Oca MR, Bhattacharya S, Vitali N, et al. THE ANTI-BCMA ANTIBODY-DRUG CONJUGATE GSK2857916 DRIVES IMMUNOGENIC CELL DEATH AND IMMUNE- MEDIATED ANTI-TUMOR RESPONSES, AND IN COMBINATION WITH AN OX40 AGONIST POTENTIATES IN VIVO ACTIVITY. HemaSphere. 2019;3:231 [Abstract #PF558, EHA 2019 24th Annual Congres.
[114] Tannir NM, Forero-Torres A, Ramchandren R, et al. Phase i dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma. Invest. New Drugs. 2014;32:1246–1257.
[115] Trudel S, Lendvai N, Popat R, et al. Targeting B-cell maturation antigen with GSK2857916 antibody–drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial. Lancet Oncol. [Internet]. 2018 [cited 2019 Oct 14];19:1641–1653. Available from: https://linkinghub.elsevier.com/retrieve/pii/S147020451830576X.
[116] Trudel S, Lendvai N, Popat R, et al. Antibody–drug conjugate, GSK2857916, in

33

relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study. Blood Cancer J. [Internet]. 2019 [cited 2019 Oct 14];9:37. Available from: http://www.nature.com/articles/s41408-019-0196-6.
[117] Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21:207–221.
[118] Wijdenes J, Vooijs WC, Clément C, et al. A plasmocyte selective monoclonal antibody (B- B4) recognizes syndecan-1. Br. J. Haematol. 1996;94:318–323.
[119] Jagannath S, Heffner LT, Ailawadhi S, et al. Indatuximab Ravtansine (BT062) Monotherapy in Patients With Relapsed and/or Refractory Multiple Myeloma. Clin. Lymphoma Myeloma Leuk. [Internet]. 2019 [cited 2019 Oct 14];19:372–380. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30930134.
[120] Kelly KR, Siegel DS, Chanan-Khan AA, et al. Indatuximab Ravtansine (BT062) in Combination with Low-Dose Dexamethasone and Lenalidomide or Pomalidomide: Clinical Activity in Patients with Relapsed / Refractory Multiple Myeloma. Blood [Internet]. 2016 [cited 2019 Oct 14];128:Abstract #4486 [ASH 2016 58th Meeting]. Available from: https://ashpublications.org/blood/article/128/22/4486/101321/Indatuximab- Ravtansine-BT062-in-Combination-with.
[121] Cunningham BA, Hemperly JJ, Murray BA, et al. Neural cell adhesion molecule: Structure, immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing. Science (80-. ). 1987;236:799–806.
[122] Van Camp B, Durie BG, Spier C, et al. Plasma cells in multiple myeloma express a natural killer cell-associated antigen: CD56 (NKH-1; Leu-19). Blood [Internet]. 1990 [cited 2020 Mar 20];76:377–382. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1695113.
[123] Kraj M, Sokołowska U, Kopec-Szlȩzak J, et al. Clinicopatholgical correlates of plasma cell CD56 (NCAM) expression in multiple myeloma. Leuk. Lymphoma [Internet]. 2008 [cited 2020 Mar 20];49:298–305. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18231917.
[124] Ailawadhi S, Kelly KR, Vescio RA, et al. A Phase I Study to Assess the Safety and Pharmacokinetics of Single-agent Lorvotuzumab Mertansine (IMGN901) in Patients with Relapsed and/or Refractory CD–56-positive Multiple Myeloma. Clin. Lymphoma

34

Myeloma Leuk. [Internet]. 2019 [cited 2019 Oct 14];19:29–34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30340993.
[125] Berdeja JG, Hernandez-Ilizaliturri F, Chanan-Khan A, et al. Phase I Study of Lorvotuzumab Mertansine (LM, IMGN901) in Combination with Lenalidomide (Len) and Dexamethasone (Dex) in Patients with CD56-Positive Relapsed or Relapsed/Refractory Multiple Myeloma (MM). Blood. 2012;120:Abstract #728 [ASH 2012 54th Meeting].
[126] Ise T, Nagata S, Kreitman RJ, et al. Elevation of soluble CD307 (IRTA2/FcRH5) protein in the blood and expression on malignant cells of patients with multiple myeloma, chronic lymphocytic leukemia, and mantle cell lymphoma. Leukemia [Internet]. 2007 [cited 2020 Mar 20];21:169–174. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17051241.
[127] Polson AG, Zheng B, Elkins K, et al. Expression pattern of the human FcRH/IRTA receptors in normal tissue and in B-chronic lymphocytic leukemia. Int. Immunol. [Internet]. 2006 [cited 2020 Mar 20];18:1363–1373. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16849395.
[128] Elkins K, Zheng B, Go MA, et al. FcRL5 as a target of antibody-drug conjugates for the treatment of multiple myeloma. Mol. Cancer Ther. [Internet]. 2012 [cited 2020 Mar 20];11:2222–2232. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22807577.
[129] Li J, Stagg NJ, Johnston J, et al. Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing. Cancer Cell [Internet]. 2017 [cited 2020 Mar 20];31:383–395. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28262555.
[130] Stewart AK, Krishnan AY, Singhal S, et al. Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma. Blood Cancer J. 2019;9:1–12.
[131] Pogue SL, Taura T, Bi M, et al. Targeting attenuated interferon-α to myeloma cells with a CD38 antibody induces potent tumor regression with reduced off-target activity. PLoS One. 2016;11.
[132] Nagorsen D, Bargou R, Rüttinger D, et al. Immunotherapy of lymphoma and leukemia with T-cell engaging BiTE antibody blinatumomab. Leuk. Lymphoma. 2009. p. 886–891.
[133] Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus Chemotherapy for

35

Advanced Acute Lymphoblastic Leukemia. N. Engl. J. Med. [Internet]. 2017 [cited 2020 Mar 20];376:836–847. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1609783.
[134] Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. [Internet]. 2015 [cited 2019 Oct 14];16:57–66. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1470204514711702.
[135] Hipp S, Tai YT, Blanset D, et al. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia [Internet]. 2017 [cited 2020 Mar 20];31:1743–1751. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28025583.
[136] Topp MS, Duell J, Zugmaier G, et al. Anti-B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma. J. Clin. Oncol. [Internet]. 2020 [cited 2020 Mar 20];38:775–783. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31895611.
[137] Cho S-F, Lin L, Xing L, et al. Anti-Bcma BiTE® AMG 701 Potently Induces Specific T Cell Lysis of Human Multiple Myeloma (MM) Cells and Immunomodulation in the Bone Marrow Microenvironment. Blood [Internet]. 2018;132:Abstract #592 [ASH 2018 60th Meeting]. Available from: http://www.bloodjournal.org/user/logout?current=node/382596.
[138] Seckinger A, Delgado JA, Moser S, et al. Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment. Cancer Cell [Internet]. 2017 [cited 2020 Mar 20];31:396–
410. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28262554.
[139] Costa LJ, Wong SW, Bermúdez A, et al. First Clinical Study of the B-Cell Maturation Antigen (BCMA) 2+1 T Cell Engager (TCE) CC-93269 in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Interim Results of a Phase 1 Multicenter Trial. Blood. 2019;134:Abstr. 143 [Updated results presented at ASH 2019].
[140] Raje NS, Jakubowiak A, Gasparetto C, et al. Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory

36

Multiple Myeloma (RRMM). Blood [Internet]. 2019 [cited 2019 Dec 13];134:Abstract #1869 [ASH 2019 61st Meeting]. Available from: https://ash.confex.com/ash/2019/webprogram/Paper121805.html.
[141] Cooper D, Madduri D, Lentzsch S, et al. Safety and Preliminary Clinical Activity of REGN5458, an Anti-Bcma x Anti-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma. Blood. 2019;134:Abstract #3176 [ASH 2019 61st Meeting].
[142] D’agostino M, Bertamini L, Oliva S, et al. Pursuing a curative approach in multiple myeloma: A review of new therapeutic strategies. Cancers (Basel). MDPI AG; 2019.
[143] Kumar SK, Dimopoulos MA, Kastritis E, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia [Internet]. 2017 [cited 2018 Jan 24];31:2443–2448. Available from: http://www.nature.com/doifinder/10.1038/leu.2017.138.
[144] Cornell RF, Gandhi UH, Lakshman A, et al. Subsequent Treatment Outcomes of Multiple Myeloma Refractory to CD38-Monoclonal Antibody Therapy. Blood. 2018;132:Abstract #2015 [ASH 2018 60th Meeting].
[145] Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia [Internet]. 2019 [cited 2020 Mar 20];33:2266–2275. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30858549.
[146] Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy- assessment and management of toxicities. Nat. Rev. Clin. Oncol. Nature Publishing Group; 2018. p. 47–62.
[147] Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N. Engl. J. Med. 2019;380:1726–1737.
[148] Chari A, Vogl DT, Jagannath S, et al. Selinexor-Containing Regimens for the Treatment of Patients with Multiple Myeloma Refractory to Chimeric Antigen Receptor T-Cell (CAR- T) Therapy. Blood. 2019;134:Abstract #1854 [ASH 2019 61st Meeting].
[149] Munshi NC, Avet-Loiseau H, Rawstron AC, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: A meta-analysis. JAMA Oncol. 2017;3:28–35.
[150] Landgren O, Devlin S, Boulad M, et al. Role of MRD status in relation to clinical outcomes

37

in newly diagnosed multiple myeloma patients: A meta-analysis. Bone Marrow Transplant. 2016;51:1565–1568.
[151] Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet [Internet]. 2019 [cited 2019 Aug 29];394:29–38. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673619312401.
[152] Mateos M-V, Dimopoulos MA, Cavo M, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N. Engl. J. Med. 2018;378:518–528.
[153] Facon T, Kumar S, Plesner T, et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N. Engl. J. Med. [Internet]. 2019 [cited 2019 Aug 30];380:2104–2115. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1817249.
[154] Gay F, Cerrato C, Rota Scalabrini D, et al. Carfilzomib-Lenalidomide-Dexamethasone (KRd) Induction-Autologous Transplant (ASCT)-Krd Consolidation Vs KRd 12 Cycles Vs Carfilzomib-Cyclophosphamide-Dexamethasone (KCd) Induction-ASCT-KCd Consolidation: Analysis of the Randomized Forte Trial in Newly Di. Blood. 2018;132:Abstract #121 [ASH 2018 60th Meeting].
[155] Ghobrial IM, Liu CJ, Redd RA, et al. A phase Ib/II trial of the first-in-class anti-CXCR4 antibody ulocuplumab in combination with lenalidomide or bortezomib plus dexamethasone in relapsed multiple myeloma. Clin. Cancer Res. [Internet]. 2020 [cited 2020 Mar 26];26:344–353. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31672767.
0 Mar 26];26:344–353. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31672767.

Annotated bibliography

*[24] Lonial S, Van de Donk N, Popat R, et al. A Phase 1b/2a Study of the CELMoD Iberdomide (CC-220) in Combination With Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. Clin. Lymphoma Myeloma Leuk. 2019;19:e52-e53 [Abstract, IMWG 2019 Meeting]. An important phase I/II trial on the new-generation immunomodulatory agent CC-220, which seems to be promising for the treatment of lenalidomide-refractory patients.

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*[44] Moreau P, Harrison S, Cavo M, et al. Updated Analysis of Bellini, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. Blood. 2019;134:Abstract #1888 [ASH 2019 61st Meeting]. A phase III trial evaluating venetoclax in combination with bortezomib and dexamethasone, paving the way for personalized therapy in the treatment of t(11;14)- positive patients.

*[63] Lee HC, Shah JJ, Feng L, et al. A phase 1 study of filanesib, carfilzomib, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Blood Cancer
J. Nature Publishing Group; 2019. Preliminary results regarding the combination of filanesib with a backbone regimen for the treatment of relapsed/refractory patients.

*[69] Chari A, Vogl DT, Gavriatopoulou M, et al. Oral Selinexor–Dexamethasone for Triple- Class Refractory Multiple Myeloma. N. Engl. J. Med. [Internet]. 2019 [cited 2020 Mar 19];381:727–738. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1903455. Promising efficacy of selinexor in combination with dexamethasone for the treatment of heavily pretreated refractory patients.

*[96] Raab MS, Engelhardt M, Blank A, et al. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1–2a trial. Lancet Haematol. 2020;7:e381–e394. Primary analysis showing a good tolerability of MOR202 and its promising efficacy in combination with immunomodulatory drugs.

**[117] Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21:207–221. A phase II study showing anti-myeloma activity with a manageable safety profile of single-agent belantamab mafodotin in relapsed/refractory multiple myeloma patients, paving the way for its further combination with backbone agents.
**[136] Topp MS, Duell J, Zugmaier G, et al. Anti-B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma. J. Clin. Oncol. [Internet]. 2020 [cited 2020 Mar 20];38:775–783. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31895611. Early results of a phase I study on 42 relapsed/refractory patients treated with the BCMA BTE AMG 420, with a high rate of deep responses and good tolerability.

Tables

Table 1. Results of the main phase I/II clinical trials with small molecules on RRMM patients
Study Agent Schedule N Previous lines median
(range) Toxicity (G≥3 AEs) ORR Median PFS
(months)
NCT01794520 [42] Venetoclax single agent 66 5 (1-15) Thrombocytopenia 26%
Neutropenia 21% 21%
*40% in t(11;14) TTP 2.6
*6.6 in t(11;14)
NCT01794507
[43] Venetoclax +Vd 33 3 (1-13) Thrombocytopenia 29%
Neutropenia 14% 67% TTP 9.5
NCT02899052 [45] Venetoclax +Kd 42 2 (1-3) Neutropenia 14%
Hypertension 12% 78%
*100% in t(11;14) -
NCT03314181
[46] Venetoclax +Dara-dex
in t(11;14) 24 2.5 (1-8) Neutropenia 13%
Hypertension 8% 92% -
NCT01478581
[51] Ibrutinib +dex 43 4 (2-10) Anemia 9%
Thrombocytopenia 9% 5% 4.6
NCT02902965
[52] Ibrutinib +Vd 76 – Thrombocytopenia 34%
Infections 43% 57% 8.5
NCT01962792 [55] Ibrutinib +Kd 84 3 (2-10) Thrombocytopenia 26%
Anemia 17%
Hypertension 19%
Diarrhea 10% 71% 7.4
NCT00821249 [60] Filanesib single agent

8 Neutropenia 49%
Thrombocytopenia 49%
Anemia 44% 16%

2.8
NCT01248923
[62] Filanesib +Vd 55 3 (1-9) Neutropenia 45%
Thrombocytopenia 29% 20% -
NCT01372540
[63] Filanesib +Kd 64 5 (1-13) Neutropenia 33%
Thrombocytopenia 72% 37% 4.8
NCT02384083
[65] Filanesib +Pd 33 3 (2-6) Neutropenia 60% 65% 7
NCT02336815
[69] Selinexor +dex 123 7 (3-18) Thrombocytopenia 59%
Anemia 44% 26% 3.7
41

Hyponatremia 22%
Neutropenia 21%
NCT02343042
[70] Selinexor +Vd 42 3 (1-11) Thrombocytopenia 46%
Neutropenia 24% 63% 9
NCT02343042
[72] Selinexor +Kd 12 4 (2-8) Thrombocytopenia 58%
Pneumonia 17% 75% -
NCT02343042
[71] Selinexor +Pd 48 4 (2-13) Thrombocytopenia 33%
Neutropenia 54% 56% 12.2
NCT02343042
[73] Selinexor +Dara 13 4 (2-10) – 76% -
NCT01096342 [78] Dinaciclib single agent 29 4 (1-5) Neutropenia 13%
Diarrhea 13%
Blurred vision 13% 11% 3.5
NCT03110822
[81] Ruxolitinib +Rp 28 6 Anemia 18%
Thrombocytopenia 14% 38% -
Abbreviations. RRMM, relapsed/refractory multiple myeloma; ORR, overall response rate; PFS, progression- free survival; G, grade, AEs, adverse events; N, number; TTP, time to progression; Vd, bortezomib- dexamethasone; Kd, carfilzomib-dexamethasone; Pd, pomalidomide-dexamethasone: Dara, daratumumab; dex, dexamethasone; Rp, lenalidomide-methylprednisolone.

1 Table 2. Results of the main phase I/II clinical trials with immunotherapy agents on RRMM patients
Drug category Study [reference] Agent Schedule (MTD/R2TD/MAD) N of patients Prior lines, median

(range) Toxicities (DLT and G3-4 AEs and AEs of
special interest) ORR PFS
median (months)
NCT01421186 [96] MOR202 +dex (no MTD) 18 3 No DLT 28% 8.4
(anti-CD38)
G3-4 AEs:

+Rd (no MTD) 17 2 – 39-59%% 65% NR
lymphopenia,
- 22-71%%
+Pd (no MTD) 21 3 48% 17.5
neutropenia
mAbs – 17-24%
thrombocytopenia

IRRs 5-11% (G1-2)
NCT03439280 [98] TAK-079 single agent (no 34 3 (2-12) No DLT 56% 3.7
(anti-CD38) MTD) *21% prior G3-4 AEs: (dose 300 mg) (dose 300 mg)
anti-CD38 – 3.5% neutropenia,
mAb – 3.5% anemia. 33%
(dose 600 mg)

NCT03340883 [104] BION-1301
(anti-APRIL) Phase I:
single agent 15 6 (4-17) No DLT 0
*36% SD -
Phase II:

+dex 36% TEAEs (36%):
- anemia (n=3),
- arthralgia (n=2),
- dysgeusia (n=2).
1 IRRs G3
NCT02666209 [154] Ulocuplumab (anti- CXCR4) Cohort A: Rd (n=30) Cohort B: Vd (n=16) 46 3 G3-4 AEs:
- neutropenia (30% in Cohort A, 6.3% in Cohort B),
- thrombocytopenia (16% in Cohort A, 18% Cohort B). 55% in Cohort A
- 16% of pts achieving ≥CR

25% in Cohort B 22.3 months in Cohort A

ADCs NCT02064387 (DREAMM-1) [115,116] Belantamab mafodotin (Anti-BCMA

+MMAF) single agent (R2TD 3.4 mg/kg) 38 part 1
35 part 2 Part 1: 76%
≥5 lines, 24% prior Dara

Part2 57% ≥
5 lines, 34% prior Dara No DLT
G3-4 AEs in 83% pts:
- thrombocytopenia 34% (in parts 1 and
2),
- anemia (16% in part 1 and 14% in part 2).

Corneal events 63% (G1-2) in part 2

RR 23% in part2 60% Part 1

Part2 12
NCT03525678 (DREAMM-2) [117] Belantamab mafodotin (Anti-BCMA
+MMAF) Belantamab mafodotin
2.5 mg/kg 97 7 (3-21) G3-4 AEs:
keratopathy 27%,
thrombocytopenia 20%,
anemia 20%,
pneumonia 4%.

dose reduction (29%)

IRRs 18% (mostly G1- 2) 31%
*19% ≥VGPR 2.9

Belantamab mafodotin
3.4 mg/kg 99 6 (3-21) G3-4 AEs:
keratopathy 21%,
thrombocytopenia 33%,
anemia 25%,
pneumonia 11%.
IRR 15% 30%
*20% ≥VGPR 4.9
NCT00723359 [119] Indatuximab Ravtansine
(Anti-CD138 +DM4) single agent
(MAD 200 mg/sqm) 31 7 (1-15) 2 DLTs
TEAEs 88% (mostly G1-2):
diarrhea, fatigue,
nausea, and anemia. 3.2%
*67% SD -
NCT01001442 [119] Indatuximab Ravtansine
(Anti-CD138 +DM4) single agent
(MAD 160 mg/sqm) 34 5 (2-13) DLTs 14% of cases
TEAEs 88%, mostly G1-2;
AEs similar to those
with single dose 5.9%
*61% SD 3
NCT01638936 [120] Indatuximab Ravtansine
(Anti-CD138 +DM4) +Rd 47
(38 pts
treated with R2TD 100
mg/m²) – 90% of AEs: G1-2;
most common: diarrhea, fatigue, and nausea. 77% 16.4

(treated with R2TD) – 79% NR
NCT00991562 [124] Lorvotuzumab mertansine (LM, IMGN901)
(Anti CD56
+mertansine) single agent
(MTD 112 mg/sqm) 37 >3 lines PN 5.3% 6% 6.5
NCT00991562 [125] Lorvotuzumab mertansine (LM, IMGN901) (Anti-CD56
+mertamsine) + Rd
(MTD 75 mg/sqm) 44 2 (1-11) PN 55% at MTD,

42% G1-2 PN if R2TD

phase

G3 PN in 1 pt, G3 TLS in 2 pts. 59% -
NCT01432353 [130] DFRF4539A
(Anti-FcRH5 – MMFE) single agent (no MTD) 39 6 (2-13) G3-4 AEs 39%:

BTEs NCT02514239 [135] AMG 420
(Anti-BCMA-CD3) single agent (MTD 800 mg/d) 42 5 DLT at 800 mg/d

TRAEs:
G3 PN in 2 pts,
G3 edema in 1 pt,
no G≥3 CNS toxicities, ORR 31%

At MTD 70% -
NCT03486067 [138] CC-2293269 (Anti-BCMA IgG1 2+1 T-cell engager) single agent 30 6 (3-12) – CRS 76% (1 G≥3).

5 Abbreviations. RRMM, relapsed/refractory multiple myeloma; mAbs, monoclonal antibodies; ADCs, antibody drug-conjugates; BTEs, Bispecific T-cell engagers; BCMA,
6 B-cell maturation antigens; APRIL, A proliferation-inducing ligand; pts, patients; DLT, dose limiting toxicity; MTD, maximum tolerated dose; MAD, maximum
7 administered Dose; G, grade; AE, adverse event; dex, dexamethasone; Rd, lenalidomide-dexamethasone; Vd, bortezomib-dexamethasone; Pd, pomalidomide-
8 dexamethasone; MMAF, monomethyl auristatin F; Dara, daratumumab; ORR, overall response rate; SD, stable disease; PR, partial response; VGPR, very good partial
9 response; CR, complete response; MRD, minimal residual disease; TEAEs, treatment-emergent adverse events; TRAEs, treatment-related adverse events; R2TD, phase 2

48

10 treatment dose; IRR, infusion related reaction; PN, peripheral neuropathy; CRS, cytokine release syndrome; CNS, central nervous system; TLS, tumor lysis syndrome;
11 ORR, overall response rate; PFS, progression-free survival; NR, not reached; MRD neg, minimal residual disease negativity.

Figure 1. Mechanisms of action of small molecules

JAK1 and JAK2 are intracytoplasmic tyrosine kinases that act together with several cytokine receptors. Ruxolitinib blocks JAK1 and JAK2 activity, resulting in the inhibition of the STAT pathway and leading to apoptosis. Venetoclax binds to BCL-2 antiapoptotic proteins, favoring pro-apoptotic proteins that lead to the release of cytochrome C from the mitochondria, which activates caspase-9 and apoptosis. Ibrutinib inhibits BCR downstream activation (NF-Kb) through the blockage of BTK. Selinexor blocks XPO-1 nuclear-cytoplasmic trafficking activity. Filanesib blocks the separation of chromosome during mitosis, by binding to KSP. Dinaciclib blocks cell cycle, inhibiting cyclin-dependent kinases (CDK) that play a key role in cell cycle arrest and DNA repair during mitosis.

Abbreviations. BCR, B-cell receptor; BTK, Bruton’s tyrosine kinase; NF-kB, nuclear factor kappa-light-chain- enhancer of activated B cells; JAK, Janus kinase; BCL2, B-cell lymphoma 2; XPO, exportin 1; KSP, kinase spindle protein; CDK, cyclin-dependent kinase; STAT, signal transducer and activator of transcription.

 

Figure 2. Mechanisms of action used in immunotherapy

BTEs can redirect and activate patients’ T cells that express CD3 against a tumor cell expressing a target antigen (e.g. BCMA in case of belantamab mafodotin). Naked mAbs display a variety of mechanisms of action: NK-cell recruitment to kill tumor cells (ADCC); inhibition of the target antigen activity (e.g. CD38 is a membrane ectoenzyme, whose enzyme activity is blocked by MOR202); direct killing activating the internal cellular signaling that leads to apoptosis; complement membrane attack complex formation and cellular lysis; and phagocytosis mediated by macrophages (ADCP). ADC activity is mainly carried out by conjugated drugs, which can kill target cells via direct DNA toxicity or cell cycle blockage (e.g. chromosome division).

Abbreviations. BTE, bispecific T-cell engager; CTL, cytotoxic T lymphocyte; BCMA, B-cell maturation antigen; NK, natural killer; mAb, monoclonal antibody; ADCC, antibody-dependent cell cytotoxicity; ADCP, antibody- dependent cell phagocytosis; CDC, complement-dependent cytotoxicity; ADC, antibody-drug conjugate; MMAF, monomethyl auristatin F.