Open access peer-reviewed chapter

Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma

Written By

Hanley N. Abramson

Submitted: July 22nd, 2020 Reviewed: September 25th, 2020 Published: October 30th, 2020

DOI: 10.5772/intechopen.94196

Chapter metrics overview

327 Chapter Downloads

View Full Metrics


Therapeutic measures designed to treat multiple myeloma (MM) have undergone a fundamental shift over the past two decades as a number of small molecules that attack this cancer by different mechanisms, including proteasome blockade, immunomodulation, and histone deacetylase (HDAC) inhibition, have been introduced. The insertion of monoclonal antibodies (mAbs) into the mix began in 2015 with the U.S. Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, which target CD38 and SLAMF7, respectively. In 2020, they were joined by another anti-CD38 mAb, isatuximab, and the bispecific antibody-drug conjugate (ADC) belantamab mafodotin, which targets the B-cell maturation antigen (BCMA). This review focuses on additional mAbs currently under clinical study for MM. These include several BCMAxCD3-directed bispecifics (AMG 420, AMG 701, REGN5458, REGN5459, teclistamab, and TNB-383B), the ADCs indatuximab ravtansine and STRO-001, and checkpoint inhibitors, although the future status of the latter is in a state of flux due to toxicity issues that arose in trials in which these drugs, especially PD-1 or PD-L1 blockers, were combined with immunomodulators.


  • CD38
  • B-cell maturation antigen
  • daratumumab
  • elotuzumab
  • isatuximab
  • belantamab mafodotin
  • indatuximab ravtansine
  • STRO-001

1. Introduction

Multiple myeloma (MM), a malignancy of plasma cells, ranks second among all blood cancers in the U.S., representing about 1% of all diagnosed malignancies. In 2020, an estimated 32,270 individuals (54.3% male), the majority over age 65, will be diagnosed with the disease and approximately 12,830 will succumb to it [1]. Classical symptoms of active MM include hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) and often are preceded by an asymptomatic stage referred to as monoclonal gammopathy of undetermined significance (MGUS). The risk of progression from MGUS to MM is about 1% per year [2] and may include another asymptomatic state known as smoldering myeloma [3]. Current guidelines for the diagnosis and treatment of MM have been published by the National Comprehensive Cancer Network (NCCN) [4]. Treatment modalities for MM have seen enormous advances since the beginning of the current century with the introduction of drugs working by different mechanisms, e.g., proteasome inhibition (bortezomib, carfilzomib, and ixazomib) and immunomodulation (lenalidomide and pomalidomide), which were added to the long-established treatments based on alkylating agents (melphalan and cyclophosphamide) and corticosteroids (dexamethasone). These measures, together with autologous stem cell transplantation (ASCT), first introduced for MM in the 1990’s, have increased the five-year survival rate for the disease from 24% in the mid-1970s to 55% in the 2010–2016 period [5]. Furthermore, the relatively recent arrival on the scene of monoclonal antibodies (mAbs), beginning with the U.S. Food and Drug Administration (FDA) approval of daratumumab in 2015, has greatly expanded the therapeutic options available to treat MM. However, in spite of these advances, MM remains incurable as patient relapse and refractoriness to treatment continue as major issues. This review focuses on the contributions made by those mAbs currently approved for MM, as well as on those under investigation as potential future therapies for this disease.


2. mAbs targeting CD38

CD38 is a multifunctional 45 kDa type II transmembrane glycoprotein, lacking an internal signaling domain, that is expressed at high levels on both malignant and normal plasma cells and has attracted much interest as a target for drug development in MM [6]. It also is found normally, but at lower levels, on the surfaces of T and B lymphocytes, natural killer (NK) cells, and monocytes. Among its several roles, CD38 acts as a receptor for CD31 (platelet endothelial cell adhesion molecule; PECAM-1) [7] and as a cyclic ADP ribose hydrolase, an ectoenzyme whose reaction products play an essential role in regulation of intracellular calcium levels [8].

Antibodies directed against CD38 kill myeloma cells by a number of possible mechanisms, chief among them being antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). Intracellular signal cascade disruption, the result of crosslinks formed between myeloma cell CD38 and Fcγ receptors on effector cells, may also play an important role in initiating apoptotic events in myeloma cells [9]. In addition, anti-CD38 antibodies have been shown to exhibit immunomodulatory effects that cause blockage of regulatory T- and B-cells and myeloid-derived suppressor cells [10].

Daratumumab (Darzalex®), a fully human IgG1κ mAb targeting CD38, initially was approved for the management of MM in patients who had relapsed following at least three prior therapies including an immunomodulator and a proteasome inhibitor [11]. Approval was supported by the results of two phase III trials - POLLUX (NCT02076009) and CASTOR (NCT02136134) - in which daratumumab/dexamethasone was combined respectively with either lenalidomide [12] or bortezomib [13]. Further encouraging data from phase III trials, demonstrating deeper and more sustained responses combined with good tolerability, soon enabled daratumumab/corticosteroid combinations with immunomodulators or proteasome inhibitors to assume an important role in even earlier courses of treatment [14, 15], as well as in newly diagnosed patients, whether ASCT-eligible [16] or -ineligible [17, 18]. Several network meta-analytic studies of random controlled trials covering a number of different settings, including in patients with newly diagnosed disease, have demonstrated the benefits of daratumumab-containing regimens in MM therapy with respect to efficacy and safety [19]. Furthermore, several reports have indicated the efficacy of daratumumab monotherapy in patients who have failed earlier lines of anti-myeloma therapy [20], as well as in patients with smoldering MM [21]. Also, the FDA recently has approved a subcutaneous formulation of daratumumab plus hyaluronidase, which enables shorter infusion times without compromising safety or efficacy [22].

Isatuximab (Sarclisa®, SAR650984) is a chimeric mouse-human IgG1κ CD38-targeting mAb that was approved by the FDA in March 2020 for the treatment of relapsing and/or refractory MM (RRMM) in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor [23]. Approval was predicated primarily on the results of the phase III ICARIA-MM trial (NCT02990338) in which addition of isatuximab to a pomalidomide/dexamethasone regimen resulted in a five month increase in median progression free survival (PFS), from 6.5 to 11.5 months [24]. Upper respiratory infections and diarrhea were the most frequently encountered adverse events noted in both groups. Although infusion reactions (mostly, grades 1 and 2) were reported in 38% of patients in the isatuximab cohort, this reaction was not noted in any patients in the pomalidomide/dexamethasone group. An additional five phase III trials that include isatuximab/dexamethasone currently are in progress for: newly diagnosed MM (NDMM) (NCT03617731 and NCT03319667 IMROZ - lenalidomide/bortezomib; NCT04483739 - lenalidomide/carfilzomib); RRMM (NCT03275285 IKEMA - carfilzomib); and high-risk smoldering MM (NCT04270409 - lenalidomide).

The mechanism of action of isatuximab exhibits some significant differences from that of daratumumab. For example, the former appears to work principally through ADCC with only minor contributions from CDC [25]. Also, unlike daratumumab, crosslinking induced by isatuximab is not a prerequisite for initiation of target cell apoptosis [26]. Moreover, isatuximab is a much more potent inhibitor of ectoenzyme activity although the significance of this is unknown [27].

MOR202 (MOR03087, TJ202) is a fully humanized IgG1λ mAb that exhibited an objective response rate (ORR) of 29% in a phase II trial with dexamethasone in patients who had previously received four lines of therapy [28]. In addition, this drug has shown some promising efficacy when combined with immunomodulators [29, 30]. MOR202 also appears to offer the advantage of requiring reduced infusion times and is associated with reduced infusion-related reactions compared to daratumumab or isatuximab, possibly due to its lack of dependency on CDC as a function of its activity. However, the drug’s sponsor, MorphoSys AG, recently decided to discontinue further development of MOR202 for MM. Two additional anti-CD38 mAbs from Takeda Oncology currently are in the early stages of clinical development for RRMM: TAK-573, an IgG4 antibody conjugated to an attenuated form of interferon α [31], and TAK-079, a fully humanized IgG1λ mAb [32].


3. mAbs targeting SLAMF7

A group of surface proteins belonging to the signaling lymphocytic activation molecule family (SLAMF) has elicited considerable interest in recent years due to the high expression of four family members (SLAMF2, 3, 6, and 7) on both normal plasma cells and those from MM patients at all stages of disease. No trials of SLAMF2-targeting mAbs have been initiated and clinical studies of the SLAMF3 and SLAMF6 mAbs SGN-CD48A and azintuxizumab vedotin (ABBV-838), respectively, both were halted early in phase I trials. On the other hand, SLAMF7 (CS1 or CD319) has emerged as the principal focus for new anti-myeloma mAb development in this group of targets with the introduction of elotuzumab (Empliciti®), a humanized IgG1κ mAb [33]. Preclinical studies revealed that the anti-myeloma activity of elotuzumab is the result of ADCC involving direct activation and engagement of NK cells [34]. FDA approval in 2015 of elotuzumab, which lacks activity as a single agent, was the result of the ELOQUENT-2 trial (NCT01239797) involving 646 randomly assigned RRMM patients who received the mAb plus dexamethasone with or without lenalidomide. The cohort receiving elotuzumab exhibited a PFS of 19.4 months and an ORR of 68% at one year and 41% at two years, compared to 14.9 months and 57% and 27% for the control [35]. These results were confirmed further by a subsequent four-year follow-up study [36]. Similar benefits of elotuzumab in RRMM were observed in combination with pomalidomide-dexamethasone in the ELOQUENT-3 trial (NCT02654132) [37], which included patients refractory to both lenalidomide and a proteasome inhibitor and resulted in the 2018 FDA approval of this combination [38]. Favorable data also have been generated in a trial (NCT01478048) in which bortezomib-dexamethasone was included with elotuzumab [39].


4. BCMA-targeting antibody-drug complexes

The cytokines BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand) have received much attention in recent years for their roles in the pathophysiology of autoimmune diseases [40]. In addition, there is evidence that these two homologous members of the tumor necrosis factor (TNF) superfamily play roles in myeloma cell viability and proliferation [41]. Two other TNF family members - transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), located on the surface of myeloma cells, serve as ligands for both BAFF and APRIL [42]. While the respective BAFF and APRIL inhibitors, atacicept and tabalumab (LY2127399), as well as the anti-APRIL mAb BION-1301, showed poor efficacy in MM trials [43, 44, 45], BCMA has surfaced as a compelling target in anti-myeloma drug research [46].

BCMA normally plays a key role in B-cell differentiation into plasma cells [47]. Myeloma cells, whether from cell lines or patient samples, exhibit not only consistent and virtually exclusive elevation of BCMA levels and its mRNA during malignant transformation but also at similar levels during the various stages of MM from previously untreated to relapse [48]. A soluble form of BCMA (sBCMA), which results from the shedding of BCMA from the plasma cell surface by the action of γ-secretase, is an important factor that, by lowering the density of the target antigen while also providing a soluble decoy, potentially limits the efficacy of BCMA blockers in clinical development, accounting for the inclusion of γ-secretase inhibitors in a number of BCMA-targeted trials [49].

Removal of several of the fucosyl groups normally found in the N-linked biantennary complex oligosaccharides in the Fc region of IgG antibodies is a well-established approach for enhancing ADCC through binding of FcγIIIa receptors on NK cells [50]. One such anti-BCMA mAb is the afucosylated antibody-drug conjugate (ADC) belantamab mafodotin (Blenrep®, GSK2857916), in which the antibody is coupled to the microtubule inhibitor monomethylauristatin F (MMAF) through a protease-resistant maleimidocaproyl linker. While the antibody component disrupts BAFF/APRIL myeloma cell signaling by binding to the BCMA receptor to induce ADCC, the MMAF component causes cell cycle arrest at the G2/M interface [51]. Belantamab mafodotin continues to be the subject of the DREAMM series of trials in RRMM patients. An early exploratory study (NCT02064387, DREAMM-1) found an ORR of 60% in 35 heavily pre-treated RRMM patients when the immunoconjugate was used as a single agent [52]. This encouraging response level dropped to 31% (30/97) in RRMM patients refractory to proteasome inhibitors, immunomodulators, and/or anti-CD38 therapy, who received the drug as monotherapy at 2.5 mg./Kg. in the ensuing phase II DREAMM-2 trial (NCT03525678) [53]. However, the efficacy level was considered comparable to that observed with other therapies for RRMM patients with similar numbers of prior therapies. Analysis of adverse event data in the DREAMM-2 trial concluded that belantamab mafodotin exhibits an acceptable safety profile with ocular toxicity, primarily in the form of keratopathy as the most commonly reported adverse event and attributable to the microtubule-inhibitor payload [54], presenting the greatest concern. Based on these data, in August, 2020, belantamab mafodotin was approved by the FDA, under the provisions of accelerated review, as monotherapy for RRMM patients who have received at least four prior treatments that included an immunomodulator, a proteasome inhibitor, and an anti-CD38 monoclonal antibody [55]. In addition to these two milestone studies, a phase II trial (NCT04126200; DREAMM-5) has been initiated that includes belantamab mafodotin monotherapy with two T-cell costimulatory agonist mAbs – the OX40-targeting GSK3174998 and the inducible co-stimulator (ICOS) GSK3359609, along with nirogacestat (PF-03084014), a γ-secretase inhibitor [56]. The ADC plus low-dose dexamethasone also is incorporated into four phase III investigations that include standard therapies such as: pomalidomide (NCT04162210; DREAMM-3, RRMM); bortezomib and daratumumab (NCT04246047; DREAMM-7, RRMM); pomalidomide and bortezomib (NCT04484623; DREAMM-8, RRMM); and lenalidomide and bortezomib (NCT04091126; DREAMM-9, NDMM) [57].

Another BCMA-targeted ADC that has elicited much interest for its anti-myeloma action is MEDI2228, which is comprised of a fully human mAb attached to a minor-groove binding pyrrolobenzodiazepine (tesirine) payload via a protease-cleavable valine-alanine linker [58]. Release of the warhead following internalization of the immunoconjugate and trafficking to the lysosome results in DNA damage and subsequent apoptosis. Preclinical studies in mice revealed this agent’s potent anti-myeloma activity even when clinically significant levels of sBCMA were present [59]. Currently, MEDI2228 is the subject of a phase I clinical trial (NCT03489525) to determine appropriate dosing as monotherapy in RRMM patients; however, no results have been reported as yet. Another anti-BCMA ADC that has entered clinical studies for MM is AMG 224 (NCT02561962), comprised of a maytansine analog connected to a non-cleavable 4-(N-maleimidomethyl) cyclohexane-1-carboxylate linker [60]. CC-99712 is yet another BCMA-targeted ADC (undisclosed composition) that recently entered a clinical trial (NCT04036461) for RRMM. Other anti-BCMA ADC mAbs that have demonstrated promise in preclinical work but for which human studies have not yet begun include two proprietary products, referred to as BCMA-077 and BCMA-024 [61], and HDP-101, in which the conjugate is the potent RNA polymerase II subunit A (POLR2A) inhibitor α-amanitin [62].


5. T-cell-engaging bispecific antibodies

The T-cell-engaging bispecific antibody (T-BsAb) concept, originally developed by Nisonoff in 1961 [63], is based on the design of a dual-targeting antibody whereby one arm initially binds to the T-cell CD3 co-receptor complex while the other arm is subsequently directed to a tumor-associated antigen. The immunological synapse created between the two cells causes release of two cytolytic-initiating proteins: perforin, which causes formation of transmembrane pores in the malignant cell and granzyme B, which traverses the pores thus produced to initiate tumor cell apoptosis. The T-BsAb strategy differs from normal T-cell mediated cytotoxicity by removing requirements for costimulatory signals, formation of an antigen-major histocompatibility complex (MHC), and for ex vivoT-cell manipulation, thus permitting the possibility of “off-the-shelf” product manufacture. Furthermore, persistent T-cell activation enables polyclonal expansion of T memory cells. In addition, the therapeutically relevant properties of constructs may be fine-tuned to optimization by altering biodistribution characteristics and the relative binding affinities of each arm for their respective targets [64].

Amgen’s proprietary BiTE® platform represents an innovative subclass of T-BsAb in which tandem single-chain variable fragments (scFvs) provide the cross-link [65]. The first successful application of BiTE® technology was the CD3-CD19 cross-linking construct blinatumomab (Blincyto®), which was approved by the FDA in 2014 for Philadelphia chromosome-negative B-cell precursor acute lymphocytic leukemia (B-cell ALL). Although a single trial (NCT03173430) of blinatumomab in RRMM patients had to be terminated because of “slow patient accrual”, the majority of myeloma-related work using BiTE® constructs have been based on recombinant antibodies designed to cross-link surface tumor-specific T-cell CD3ζ chains and targeted myeloma cell BCMA.

Initial results with the BCMAxCD3 BiTE® product AMG 420 (BI-836909), which was accorded fast-track status by the FDA in 2018, showed an ORR of 31% in 42 RRMM patients, including seven of ten patients refractory to at least two lines of therapy who received the maximum tolerated dose of 400 μg/day. Infections and polyneuropathy were the most serious adverse events noted in this trial. Cytokine release syndrome (CRS; cytokine storm), predominantly grade 1, was observed in 38% of patients in the study [66, 67]. Monotherapy with AMG 701, a related BiTE® construct with a longer serum half-life than AMG 420, currently is the focus of a phase I trial (NCT03287908) for RRMM. Data generated in a preclinical investigation suggests that future consideration of a trial of AMG 701 in combination with an immunomodulator may be warranted [68]. In addition, two other BCMAxCD3 bispecific antibodies from Regeneron, REGN5458 (NCT03761108) and REGN5459 (NCT04083534), are in phase I RRMM studies. Preliminary data on the first three patients treated with the former agent have been reported [69].

Following favorable safety results in a monkey model [70], two phase I RRMM clinical trials of the BCMAxCD3 bispecific teclistamab (JNJ-64007957) have been initiated. In addition to a dose-escalation study (NCT03145181), this agent has been incorporated into a trial (NCT04108195) that includes subcutaneous daratumumab and talquetamab (JNJ-64407564), a CD3xGPRC5D bispecific construct. Another BCMAxCD3 formatted product under scrutiny for RRMM is PF-06863135 (PF-3135) (NCT03269136), the result of hinge-mutation engineering of an IgG2a backbone [71]. CC-93269, a T-cell engager whose arms bind in a 2 + 1 arrangement, monovalently to CD3ε and bivalently to BCMA, is another member of this class in a myeloma-based trial (NCT03486067) [72].

TNB-383B, a BCMAxCD3 T-BsAb resulting from collaboration between Tenebio and Abbvie and designated as an orphan drug by the FDA, differs from other drugs in this class in that its structure consists of a single immunoglobulin light chain and two variable heavy chains. The product, which recently began a phase I trial for RRMM (NCT03933735), is noteworthy for its strong T-cell activation kinetics and low affinity anti-CD3 arm, which results in reduced release of cytokines while retaining high cytotoxicity toward myeloma cells [73]. A number of other bispecific antibodies have exhibited promise for RRMM in preclinical work. These include TNB-381 M [74], FPA-151 [74], EM801 [48], and AP163 [75]. HPN217, developed by Harpoon Therapeutics, is a tri-specific antibody possessing three binding domains in a single chain – a C-terminal single-chain CD3ε T-cell receptor-(TCR)-binding component, a human serum albumin-binding central domain, and an N-terminal BCMA-binding portion. This product, which is in a phase I/II trial for RRMM (NCT04184050), has an extended half-life compared to bispecific formats, a property ascribed to its smaller size and flexibility [76]. Moreover, bispecifics based on myeloma surface antigens other than BCMA have been developed as alternative CD3 epitope binding partners. In addition to the aforementioned talquetamab (NCT03399799) [77], these include the CD3xCD38 construct found in GBR 1342 (NCT03309111) [78] and the CD3xFcRH5 design incorporated into BFCR4350A (NCT03275103) [79].

In addition to the BCMAxCD3 bispecific formats noted above, creation of BCMA-targeted constructs directed to receptors on NK cells has been described. Like cytotoxic T-cells, NK cells are known to mediate cytotoxicity through a variety of mechanisms, including granzyme-perforin release and through expression of various apoptosis-inducing ligands [80]. A tri-specific product that binds both BCMA and CD200 on myeloma cells to CD16A on NK cells represents one such drug [81]. Similarly, CTX-4419, which binds BCMA to both NK cell CD16A and p30, has shown initial promise in preclinical models although CD16A binding does not appear to be a requirement for the anti-myeloma activity of this product [82]. Other BCMA-NK cell-engaging antibodies, such as CTX-8573 [83] and AFM26 [84], also have shown some potential as RRMM therapies.


6. Immune checkpoint inhibitors

Over the past decade, immune checkpoint blockade has emerged as a principal strategy for new antitumor drug development. This immunotherapeutic approach is based on identification of biomarkers and their cognate ligands that enable the body’s immune system to overcome the capacity of tumor cells to evade immune surveillance and elimination, as well as on the design of mAbs to block these interactions. In its most successful application to date, discoveries made concerning the roles played in this process by cytotoxic T-lymphocyte–associated protein-4 (CTLA-4), the first member of this class to serve as a clinical target, and the programmed death (PD) receptor, have given momentum to this innovative line of attack on a variety of tumor types [85].

Costimulatory signals resulting from interaction of CD28 on the surface of T-cells with its CD80 (B7–1) ligand on antigen-presenting cells play an important role in activating T-cells. CTLA-4, expressed on the T-cell plasma membrane, competes with CD80-CD28 binding to downregulate T-cell activation and thus represents an important mechanism that suppresses immune responses and, as a consequence, enables tumor cells to evade detection. CTLA-4-directed mAbs, by competing with the CD80-CD28 interaction, enhance the ability of T-cells to generate an antitumor response. This strategic approach was successfully applied to the immunotherapy of advanced melanoma by the anti-CTLA-4 mAb ipilimumab, which was approved by the FDA in 2011 and has been extended since to include a number of other solid tumors [86]. However, the drug has shown less than impressive results in hematologic cancers, such as acute myeloid leukemia [87]. One trial (NCT02681302) of ipilimumab combined with nivolumab that included both lymphoma and MM patients is currently active but so far only preliminary efficacy and toxicity data have been reported [88].

Binding of PD-1, expressed on the surface of T-cells, to PD-L1 or PD-L2 on tumor cells inhibits cytotoxic T lymphocyte proliferation and cytokine secretion while also causing an increase in the T regulatory cell population. These combined effects produce immune tolerance, enabling unrestrained tumor cell growth and survival [89]. Since 2014, the FDA has approved three PD-1 inhibitors – pembrolizumab (Keytruda®), nivolumab (Opdivo®), and cemiplimab (Libtayo®) and three PD-L1 blockers – avelumab (Bavencio®), durvalumab (Imfinzi®), and atezolizumab (Tecentriq®). Pembrolizumab, the first to be approved and the most versatile member of the checkpoint blocker group, has been approved for 17 different indications, many as front-line therapy for solid tumors ranging from melanoma to small-cell lung cancer to metastatic Merkel cell carcinoma [90]. In 2017, the FDA in an unprecedented move approved pembrolizumab for the treatment of solid tumors having a microsatellite instability (mismatched repair deficiency). Known as a tissue agnostic approach to cancer diagnosis and treatment, this marked the first drug approval based on a specific biomarker instead of on the tissue or organ of origin [91].

In terms of hematologic malignancies, pembrolizumab has been approved for treatment of Hodgkin’s lymphoma while both pembrolizumab and nivolumab have been approved for primary mediastinal large B-cell lymphoma (PMBCL). While studies of checkpoint inhibitors in both chronic and acute leukemias generally have been disappointing [87], work in the area of MM has shown some degree of efficacy but major issues concerning toxicity have arisen. Following favorable results in early phase trials [92, 93], pembrolizumab/dexamethasone was included in two phase III trials with and without the immunomodulators lenalidomide (NCT02579863—KEYNOTE-185; NDMM) and pomalidomide (NCT02576977—KEYNOTE-183; RRMM). However, in July 2017, the FDA placed clinical holds on both trials due to the higher risk of death in the cohorts receiving the PD-1 blocker [94]. This suspension soon was expanded to include partial or full holds on all myeloma trials using combinations of immunomodulators and checkpoint inhibitors, an action that later was reversed in the case of three myeloma trials that employed nivolumab (NCT03023527, NCT01592370, and NCT02612779); however, no data have been forthcoming for these resumed studies. At this point, any future role that checkpoint inhibitor-immunomodulator combinations may play in MM therapy is very much in a state of flux [95]. Other checkpoints that may serve as targets for MM but for which only limited preclinical or clinical studies are currently available include killer-cell immunoglobulin-like receptors (KIR) [96], CD47 [97], LAG3 [98], TIGIT [99, 100], and TIM-3 [101]. Table 1 contains a partial list of checkpoint inhibitors currently in clinical trials for MM.

Trial ID [reference]NTrial title
PD-1 Inhibitors
NCT03848845 [102]40A phase I/II single arm open-label study to explore safety and clinical activity of GSK2857916 administered in combination with pembrolizumab in subjects with relapsed/refractory multiple myeloma (DREAMM 4)
NCT0350636041Phase II trial of pembrolizumab, ixazomib, and dexamethasone for relapsed multiple myeloma
NCT0436185133Phase II study of daratumumab-pembrolizumab for multiple myeloma patients with ≥ three prior lines of therapy
NCT03168438 [103]20NY-ESO-1ᶜ259T alone and in combination with pembrolizumab for multiple myeloma
NCT0378206425A phase II trial of vaccination with dendritic cell (DC)/myeloma fusions in combination with nivolumab in patients with relapsed multiple myeloma
NCT03292263 [104]30Autologous stem cell transplantation with nivolumab in patients with multiple myeloma
NCT0411933650A phase II study of nivolumab in combination with ixazomib, cyclophosphamide, and dexamethasone in relapsed and refractory multiple myeloma
NCT03194867109A phase I/II study to evaluate safety, pharmacokinetics and efficacy of isatuximab in combination with cemiplimab in patients with relapsed/refractory multiple myeloma
NCT0311199226Phase I/Ib, multi-center, open-label, study of single agent CJM112 (anti-IL17A mAb), and spartalizumab (PDR001) in combination with LCL161 (SMAC mimetic) or CJM112 in patients with relapsed and/or refractory multiple myeloma
PD-L1 Inhibitors
NCT02431208 [105, 106] Trial Start: 7/22/15300A phase Ib study of the safety and pharmacokinetics of atezolizumab alone or in combination with an immunomodulatory drug and/or daratumumab in patients with multiple myeloma (relapsed/ refractory and post-autologous stem cell transplantation)
NCT0391043930A phase II pilot study of avelumab in combination with hypofractionated radiotherapy in patients with relapsed refractory multiple myeloma
CD47 Inhibitors
NCT03530683156A phase Ia/Ib dose escalation and expansion trial of TTI-622 in patients with advanced relapsed or refractory lymphoma or myeloma
LAG-3 and TIGIT Inhibitors
NCT04150965104A phase I/II assessment of combination immuno-oncology drugs elotuzumab, anti-LAG-3 (BMS-986016) and anti-TIGIT (BMS-986207)

Table 1.

Selected active trials of checkpoint inhibitors in MM.

Trial start date on or after July 1, 2017, unless otherwise noted.


7. Additional mAbs and their targets

CD138 (syndecan-1), which is overexpressed in MM [107], is the target of indatuximab ravtansine (BT-062), an ADC whose anti-CD138 mAb is linked to a cytotoxic microtubule destabilizing maytansinoid. This agent has been studied in RRMM both in combination with immunomodulators (NCT01638936) and as a single agent (NCT01001442 and NCT00723359). The 34 patients (median 5 prior therapies) in the monotherapy study who received a multi-dose regimen showed a median PFS of three months and median overall survival (OS) of 26.7 months while diarrhea and fatigue were the most commonly reported adverse events [108]. In addition, an anti-CD138 mAb, known as mAb 1610, has shown some potential anti-myeloma promise in a preclinical study [109].

CD74 plays a key role as a chaperone, enabling the proper folding and trafficking of MHC Class II proteins in antigen-presenting cells. In addition, this type II transmembrane protein activates the NFκB signaling pathway following the binding of its intracellular domain to macrophage migration inhibitory factor (MIF) and translocation to the nucleus where it induces proliferation and survival, especially in B-cells. Elevated expression of CD74 in B cell malignancies, such as non-Hodgkin’s lymphomas and MM, has made this an attractive target for these types of cancer [110]. STRO-001, which has received Orphan Drug status from the FDA, is an anti-CD74 ADC in which an aglycosylated human IgG1 antibody is conjugated to a maytansinoid linker-warhead. A phase I trial (NCT03424603) of STRO-001 in B-cell malignancies, including MM, recently was initiated [111]. Two other CD74-targeting agents, milatuzumab and its doxorubicin-linked ADC, that had been under study in MM, both have been dropped from further consideration.

Another conjugate linked to a maytansine derivative, the anti-CD56 ADC lorvotuzumab mertansine (IMGN901; BB-10901), had been the focus of a phase I trial in CD56-positive RRMM patients (NCT00346255) but insufficient efficacy and dose-related toxicity reportedly led to discontinuation of further studies of this agent [112, 113]. Other mAbs that have been dropped from further consideration in MM following demonstration of only modest efficacy and/or unacceptable toxicity in trials include the following (target in parentheses): dacetuzumab and lucatumumab (CD40); F50067 (CXCR-4); AVE1642 and figitumumab (IGF-R1); IPH 2101 (KIR); PAT-SM6 (GRP-78); BI 505 (intercellular adhesion molecule-1, ICAM-1), and siltuximab (IL-6).


8. Conclusion

The number of therapeutic options available to treat MM has witnessed a remarkable upsurge since the turn of the current century. The advent of proteasome inhibitors and immunomodulators, in addition to other small molecules working by additional mechanisms, such as histone deacetylase (HDAC) blockade and nuclear export inhibition, has resulted in a major alteration in the clinical approach to the disease. Over the past half-decade, the introduction of mAbs into the fight against this malignancy has further shifted the landscape of how this disease is treated both in newly diagnosed patients and in the relapsed/refractory setting. Chief among these newer entries are daratumumab and elotuzumab, and more recently the anti-CD38 mAb isatuximab and the bispecific antibody belantamab mafodotin. Although employment of mAbs in combination with small molecule agents, such as bortezomib and lenalidomide, has been of immense value in extending patients’ ability to achieve deep and durable remissions, relapse and refractoriness to therapy remain as major obstacles to attainment of a cure. Work on checkpoint inhibitors, which have been employed successfully in several tumor types and had shown early promise in MM, continues to move forward in clinical studies of MM, although tempered by recent setbacks stemming from toxicity concerns when used in combination with immunomodulators.

It is evident that future advances in treating MM will be dependent on gaining even deeper insight into the transformative molecular events leading to the disease. As new biomarkers that drive this unrelenting malignancy are identified, design and discovery of innovative target-based therapeutic approaches that will find their way into clinical practice will be established. The attainments already realized by the advent of mAbs, particularly daratumumab, in recent years offers some prospect for even greater success in the application of mAbs in MM over the coming decade.


  1. 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30. doi:10.3322/caac.21590
  2. 2. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346(8):564-9. doi:10.1056/NEJMoa01133202
  3. 3. Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356(25):2582-90. doi:10.1056/NEJMoa070389
  4. 4. Kumar SK, Callander NS, Hillengass J, Liedtke M, Baljevic M, Campagnaro E, et al. NCCN guidelines insights: multiple myeloma, version 1.2020. J Natl Compr Canc Netw. 2019;17(10):1154-65. doi:10.6004/jnccn.2019.0049
  5. 5. SEER Cancer Statistics Review (CSR) 1975-2017: Myeloma; National Cancer Institute: Bethesda, MD, USA, 2020
  6. 6. Jiao Y, Yi M, Xu L, Chu Q , Yan Y, Luo S, et al. CD38: Targeted therapy in multiple myeloma and therapeutic potential for solid cancers. Expert opinion on investigational drugs. 2020. doi:10.1080/13543784.2020.181425. Online ahead of print
  7. 7. Deaglio S, Morra M, Mallone R, Ausiello CM, Prager E, Garbarino G, et al. Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J Immunol. 1998;160(1):395-402. doi:
  8. 8. Aarhus R, Graeff RM, Dickey DM, Walseth TF, Lee HC. ADP-ribosyl cyclase and CD38 catalyze the synthesis of a calcium-mobilizing metabolite from NADP. J Biol Chem. 1995;270(51):30327-33. doi:10.1074/jbc.270.51.30327
  9. 9. Laubach JP, Richardson PG. CD38-targeted immunochemotherapy in refractory multiple myeloma: a new horizon. Clin Cancer Res. 2015;21(12):2660-2. doi:10.1158/1078-0432.ccr-14-3190
  10. 10. van de Donk N. Immunomodulatory effects of CD38-targeting antibodies. Immunol Lett. 2018;199:16-22. doi:10.1016/j.imlet.2018.04.005
  11. 11. McKeage K. Daratumumab: first global approval. Drugs. 2016;76(2):275-81. doi:10.1007/s40265-015-0536-1
  12. 12. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-31. doi:10.1056/NEJMoa1607751
  13. 13. Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-66. doi:10.1056/NEJMoa1606038
  14. 14. Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-97. doi:10.1016/s0140-6736(20)30734-0
  15. 15. Nooka AK, Joseph NS, Kaufman JL, Heffner LT, Gupta VA, Gleason C, et al. Clinical efficacy of daratumumab, pomalidomide, and dexamethasone in patients with relapsed or refractory myeloma: utility of re-treatment with daratumumab among refractory patients. Cancer. 2019;125:2991-3000. doi:10.1002/cncr.32178
  16. 16. Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, 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. 2019;394:29-38. doi:10.1016/s0140-6736(19)31240-1
  17. 17. Durie BGM, Kumar SK, Usmani SZ, Nonyane BAS, Ammann EM, Lam A, et al. Daratumumab-lenalidomide-dexamethasone vs standard-of-care regimens: Efficacy in transplant-ineligible untreated myeloma. Am J Hematol. 2020. doi:10.1002/ajh.25963. Online ahead of print
  18. 18. Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518-28. doi:10.1056/NEJMoa1714678
  19. 19. Musto P, La Rocca F. Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real life studies and meta-analyses. Expert Rev Hematol. 2020;13(4):331-49. doi:10.1080/17474086.2020.1740084
  20. 20. Beksac M, Aydin Y, Goker H, Turgut M, Besisik SK, Cagirgan S, et al. Early access program results from Turkey and a literature review on daratumumab monotherapy among heavily pretreated patients with relapsed/refractory myeloma. Clin Lymphoma Myeloma Leuk. 2020;20(8):e474-e84. doi:10.1016/j.clml.2020.02.017
  21. 21. Landgren CO, Chari A, Cohen YC, Spencer A, Voorhees P, Estell JA, et al. Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS). Leukemia. 2020;34(7):1840-52. doi:10.1038/s41375-020-0718-z
  22. 22. Usmani SZ, Nahi H, Mateos MV, van de Donk N, Chari A, Kaufman JL, et al. Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma. Blood. 2019;134(8):668-77. doi:10.1182/blood.2019000667
  23. 23. Dhillon S. Isatuximab: first approval. Drugs. 2020;80(9):905-12. doi:10.1007/s40265-020-01311-1
  24. 24. Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096-107. doi:10.1016/s0140-6736(19)32556-5
  25. 25. van de Donk N, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131(1):13-29. doi:10.1182/blood-2017-06-740944
  26. 26. Jiang H, Acharya C, An G, Zhong M, Feng X, Wang L, et al. SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia. 2016;30(2):399-408. doi:10.1038/leu.2015.240
  27. 27. Moreno L, Zabaleta A, Alignani D, Ajona D, Lasa M, Maiso P, et al. Critical analysis on the mechanism of action (MoA) of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma (MM). Blood. 2016;128:2105. doi:org/10.1182/blood.V128.22.2105.2105
  28. 28. Raab MS, Chatterjee M, Goldschmidt H, Agis H, Blau IW, Einsele H, et al. Phase I/IIa study of the human anti-CD38 antibody MOR202 (MOR03087) in relapsed or refractory multiple myeloma. Blood. 2015;126:3035. doi:org/10.1182/blood.V126.23.3035.3035
  29. 29. Raab MS, Chatterjee M, Goldschmidt H, Agis H, Blau I, Einsele H, et al. A phase I/IIa study of the CD38 antibody MOR202 alone and in combination with pomalidomide or lenalidomide in patients with relapsed or refractory multiple myeloma. Blood. 2016;128(22):7. doi:10.1182/blood.V128.22.1152.1152
  30. 30. Raab MS, Engelhardt M, Blank A, Goldschmidt H, Agis H, Blau IW, 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. The Lancet Haematology. 2020;7(5):e381-e94. doi:10.1016/s2352-3026(19)30249-2
  31. 31. Fatholahi M, Valencia M, Mark A, Bi MY, Syed S, Zhang YH, et al. TAK-573, an anti-CD38-targeted attenuated interferon alpha (IFN alpha) fusion protein, showed anti-myeloma tumor responses in combination with standard of care (SOC) agents in multiple myeloma (MM) xenograft tumor models in vivo. Clinical Lymphoma Myeloma & Leukemia. 2019;19(10):E116-E. doi:10.1016/j.clml.2019.09.192
  32. 32. Krishnan AY, Patel KK, Hari P, Jagannath S, Niesvizky R, Silbermann RW, 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. doi:10.1182/blood-2019-128007
  33. 33. Lamb YN. Elotuzumab: a review in relapsed and/or refractory multiple myeloma. Drugs. 2018;78(14):1481-8. doi:10.1007/s40265-018-0969-4
  34. 34. Collins SM, Bakan CE, Swartzel GD, Hofmeister CC, Efebera YA, Kwon H, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62(12):1841-9. doi:10.1007/s00262-013-1493-8
  35. 35. Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621-31. doi:10.1056/NEJMoa1505654
  36. 36. Dimopoulos MA, Lonial S, Betts KA, Chen C, Zichlin ML, Brun A, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018;124(20):4032-43. doi:10.1002/cncr.31680
  37. 37. Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379(19):1811-22. doi:10.1056/NEJMoa1805762
  38. 38. Press release (Bristol Myers Squibb - Nov. 6, 2018): U.S. Food and Drug Administration approves Empliciti® (elotuzumab) plus pomalidomide and dexamethasone, a new immunotherapy combination for certain patients with relapsed or refractory multiple myeloma
  39. 39. Jakubowiak A, Offidani M, Pegourie B, De La Rubia J, Garderet L, Laribi K, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016;127(23):2833-40. doi:10.1182/blood-2016-01-694604
  40. 40. Shabgah AG, Shariati-Sarabi Z, Tavakkol-Afshari J, Mohammadi M. The role of BAFF and APRIL in rheumatoid arthritis. J Cell Physiol. 2019;234(10):17050-63. doi:10.1002/jcp.28445
  41. 41. Pan J, Sun Y, Zhang N, Li J, Ta F, Wei W, et al. Characteristics of BAFF and APRIL factor expression in multiple myeloma and clinical significance. Oncol Lett. 2017;14(3):2657-62. doi:10.3892/ol.2017.6528
  42. 42. Xu S, Lam KP. Transmembrane activator and CAML interactor (TACI): another potential target for immunotherapy of multiple myeloma? Cancers (Basel). 2020;12(4):1045. doi:10.3390/cancers12041045
  43. 43. Rossi JF, Moreaux J, Hose D, Requirand G, Rose M, Rouille V, et al. Atacicept in relapsed/refractory multiple myeloma or active Waldenstrom's macroglobulinemia: a phase I study. Br J Cancer. 2009;101(7):1051-8. doi:10.1038/sj.bjc.6605241
  44. 44. Raje NS, Moreau P, Terpos E, Benboubker L, Grzasko N, Holstein SA, et al. Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma. Br J Haematol. 2017;176(5):783-95. doi:10.1111/bjh.14483
  45. 45. Bensinger W, Raptis A, Berenson J, Spira A, Nooka A, Chaudhry M, et al. Phase 1 study of safety and tolerability of BION-1301 in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2019;37:8012
  46. 46. Shah N, Chari A, Scott E, Mezzi K, Usmani SZ. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia. 2020;34(4):985-1005. doi:10.1038/s41375-020-0734-z
  47. 47. O'Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199(1):91-8. doi:10.1084/jem.20031330
  48. 48. Seckinger A, Delgado JA, Moser S, Moreno L, Neuber B, Grab A, et al. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment. Cancer Cell. 2017;31(3):396-410. doi:10.1016/j.ccell.2017.02.002
  49. 49. Sanchez E, Li M, Kitto A, Li J, Wang CS, Kirk DT, et al. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br J Haematol. 2012;158(6):727-38. doi:10.1111/j.1365-2141.2012.09241.x
  50. 50. Mori K, Iida S, Yamane-Ohnuki N, Kanda Y, Kuni-Kamochi R, Nakano R, et al. Non-fucosylated therapeutic antibodies: the next generation of therapeutic antibodies. Cytotechnology. 2007;55(2-3):109-14. doi:10.1007/s10616-007-9103-2
  51. 51. Tai YT, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7(11):1187-99. doi:10.2217/imt.15.77
  52. 52. Trudel S, Lendvai N, Popat R, Voorhees P.M., Reeves B, Libby III EN, et al. Deep and durable responses in patients (pts) with relapsed/refractory multiple myeloma (MM) treated with monotherapy GSK2857916, an antibody drug conjugate against B-cell maturation antigen (BCMA): Preliminary results from part 2 of study BMA117159. Blood. 2017;130:741. doi:org/10.1182/blood.V130.Suppl_1.741.741
  53. 53. Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari 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(2):207-21. doi:10.1016/s1470-2045(19)30788-0
  54. 54. Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. mAbs. 2016;8(4):659-71. doi:10.1080/19420862.2016.1156829
  55. 55. Press Release (GlaxoSmithKline - August 6, 2020): FDA approves GSK’s BLENREP (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma
  56. 56. Richardson PG, Biswas S, Holkova B, Jackson N, Netherway T, Sofia Paul S, et al. DREAMM-5 platform trial: Belantamab mafodotin in combination with novel agents in patients with relapsed/refractory multiple myeloma (RRMM). J Clinical Oncology. 2020;38(15):TPS8552. doi:10.1200/JCO.2020.38.15_suppl.TPS8552
  57. 57. Usmani SZ, Terpos E, Janowski W, Quach H, West S, Williams D, et al. DREAMM-9: Phase III study of belantamab mafodotin plus VRd versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (TI NDMM). J Clinical Oncol. 2020;38(15):TPS8556. doi:10.1200/JCO.2020.38.15_suppl.TPS8556
  58. 58. Tiberghien AC, Levy JN, Masterson LA, Patel NV, Adams LR, Corbett S, et al. Design and synthesis of tesirine, a clinical antibody-drug conjugate pyrrolobenzodiazepine dimer payload. ACS Med Chem Lett. 2016;7(11):983-7. doi:10.1021/acsmedchemlett.6b00062
  59. 59. Kinneer K, Flynn M, Thomas SB, Meekin J, Varkey R, Xiao X, et al. Preclinical assessment of an antibody-PBD conjugate that targets BCMA on multiple myeloma and myeloma progenitor cells. Leukemia. 2019;33(3):766-71. doi:10.1038/s41375-018-0278-7
  60. 60. Lee HC, Raje NS, Landgren O, Upreti VV, Wang J, Avilion AA, et al. Letter: phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma. Leukemia. 2020:4. doi:10.1038/s41375-020-0834-9
  61. 61. Hau A, Zhu T, Wang R, Lau M, Li L, Li X, et al. Preclinical development of a BCMA targeting antibody-drug conjugate with novel payload for multiple myeloma therapy. Blood. 2019;134:5623. doi:org/10.1182 blood-2019-132080
  62. 62. Singh RK, Jones RJ, Shirazi F, Hong S, Wang H, Wan J, et al. HDP-101, a novel BCMA-targeted antibody conjugated to alpha-amanitin, is active against myeloma with preferential efficacy against preclinical models of deletion 17p. Clinical Lymphoma Myeloma & Leukemia. 2019;19(10):E152-E. doi:10.1016/j.clml.2019.09.253
  63. 63. Nisonoff A, Rivers MM. Recombination of a mixture of univalent antibody fragments of different specificity. Arch Biochem Biophys. 1961;93:460-2. doi:10.1016/0003-9861(61)90296-x
  64. 64. Suurs FV, Lub-de Hooge MN, de Vries EGE, de Groot DJA. A review of bispecific antibodies and antibody constructs in oncology and clinical challenges. Pharmacol Ther. 2019;201:103-19. doi:10.1016/j.pharmthera.2019.04.006
  65. 65. Stieglmaier J, Benjamin J, Nagorsen D. Utilizing the BiTE (bispecific T-cell engager) platform for immunotherapy of cancer. Expert Opin Biol Ther. 2015;15(8):1093-9. doi:10.1517/14712598.2015.1041373
  66. 66. Topp MS, Duell J, Zugmaier G, Attal M, Moreau P, Langer C, et al. Anti-B-cell maturation antigen BiTE molecule AMG 420 induces responses in multiple myeloma. J Clin Oncol. 2020;38(8):775-83. doi:10.1200/jco.19.02657
  67. 67. Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020;70(2):86-104. doi:10.3322/caac.21596
  68. 68. Cho S-F, Lin L, Xing L, Wen K, Yu T, Wahl J, et al. AMG 701, a half-life extended anti-BCMA BiTE®, potently induces T cell-redirected lysis of human multiple myeloma cells and can be combined with IMiDs to overcome the immunosuppressive bone marrow microenvironment. Clin Lymphoma Myeloma Leuk. 2019;19(10):e54. doi:org/10.1016/j.clml.2019.09.082
  69. 69. Cooper D, Madduri D, Lentzsch S, Jagannath S, Li J, Boyapati A, 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;134:3176. doi:org/10.1182/blood-2019-126818
  70. 70. Girgis S, Shetty S, Jiao T, Amuzie C, Weinstock D, Watson RG, et al. Exploratory pharmacokinetic/pharmacodynamic and tolerability study of BCMAxCD3 in cynomolgus monkeys. Blood. 2016;128:5668. doi:org/10.1182/blood.V128.22.5668.5668
  71. 71. Raje NS, Jakubowiak A, Gasparetto C, Cornell RF, Krupka HI, Navarro D, 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 multiple myeloma (RRMM). Blood. 2019;128:1869. doi:org/10.1182/blood-2019-121805
  72. 72. Costa LJ, Wong SW, Bermúdez A, de la Rubia J, Mateos M-V, Ocio EM, 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;134:143. doi:org/10.1182/blood-2019-122895
  73. 73. Trinklein ND, Pham D, Schellenberger U, Buelow B, Boudreau A, Choudhry P, et al. Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies. mAbs. 2019;11(4):639-52. doi:10.1080/19420862.2019.1574521
  74. 74. Nie S, Wang Z, Moscoso-Castro M, D'Souza P, Lei C, Xu J, et al. Biology drives the discovery of bispecific antibodies as innovative therapeutics. Antibody therapeutics. 2020;3(1):18-62. doi:10.1093/abt/tbaa003
  75. 75. Li Z, Li Q , Zhang G, Ma X, Hu X, Ouyang K, et al. A novel bispecific BCMAxCD3 T cell-engaging antibody that treat multiple myeloma (MM) with minimal cytokine secretion. Ann Oncol. 2019;30:V808. doi: 10.1093/annonc/mdz269.038
  76. 76. Law CL, Aaron W, Austin R, Barath M, Callihan E, Evans T, et al. Preclinical and nonclinical characterization of HPN217: a tri-Specific T cell activating construct (TriTAC) targeting B cell maturation antigen (BCMA) for the treatment of multiple myeloma. Blood. 2018;132:3225. doi:org/10.1182/blood-2018-99-113921
  77. 77. Pillarisetti K, Edavettal S, Mendonça M, Li Y, Tornetta M, Babich A, et al. A T-cell-redirecting bispecific G-protein-coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma. Blood. 2020;135(15):1232-43. doi:10.1182/blood.2019003342
  78. 78. Richter JR, Landgren CO, Kauh JS, Back J, Salhi Y, Reddy V, et al. Phase 1, multicenter, open-label study of single-agent bispecific antibody T-cell engager GBR 1342 in relapsed/refractory multiple myeloma. J Clin Oncol. 2018;36(15):2. doi:10.1200/JCO.2018.36.15_suppl.TPS3132
  79. 79. Cohen AD, Trudel S, Forsberg PA, Fonseca R, Krishnan AY, Spencer A, et al. GO39775: A multicenter phase I trial evaluating the safety, pharmacokinetics, and activity of BFCR4350A, a FcRH5/CD3 T-cell dependent bispecific antibody, in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2020;38(15 supplement). doi:10.1200/JCO.2020.38.15_suppl.TPS8551
  80. 80. Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, et al. Activation of NK cell cytotoxicity. Mol Immunol. 2005;42(4):501-10. doi:10.1016/j.molimm.2004.07.034
  81. 81. Gantke T, Weichel M, Reusch U, Ellwanger K, Fucek I, Griep R, et al. Trispecific antibodies for selective CD16A-directed NK-cell engagement in multiple myeloma. Blood. 2016;128:4513. doi:org/10.1182/blood.V128.22.4513.4513
  82. 82. Draghi M, Schafer JL, Nelson A, Frye Z, Oliphant A, Haserlat S, et al. Preclinical development of a first-in-class NKp30xBCMA NK cell engager for the treatment of multiple myeloma. Cancer Res. 2019;79:4972. doi:10.1158/1538-7445.AM2019-4972
  83. 83. Watkins-Yoon J, Guzman W, Oliphant A, Haserlat S, Leung A, Chottin C, et al. CTX-8573, an innate-cell engager targeting BCMA, is a highly potent multispecific antibody for the treatment of multiple myeloma. Blood. 2019;134:3182. doi:org/10.1182/blood-2019-128749
  84. 84. Ross T, Reusch U, Wingert S, Haneke T, Klausz K, Otte AK, et al. Preclinical characterization of AFM26, a novel B cell maturation antigen (BCMA)-directed tetravalent bispecific antibody for high affinity retargeting of NK cells against myeloma. J Clin Oncol. 2018;35(15):1927. doi:org/10.1182/blood-2018-99-118970
  85. 85. Esfahani K, Roudaia L, Buhlaiga N, Del Rincon SV, Papneja N, Miller WH, Jr. A review of cancer immunotherapy: from the past, to the present, to the future. Curr Oncol. 2020;27(Suppl 2):S87-S97. doi:10.3747/co.27.5223
  86. 86. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67. doi:10.1182/blood-2017-06-741033
  87. 87. Liao D, Wang M, Liao Y, Li J, Niu T. A review of efficacy and safety of checkpoint inhibitor for the treatment of acute myeloid leukemia. Front Pharmacol. 2019;10:609. doi:10.3389/fphar.2019.00609
  88. 88. Skarbnik AP, Donato ML, Rowley SD, Goy A, Vesole DH, Munshi PN, et al. Preliminary safety and efficacy data for combined checkpoint inhibition with ipilimumab (I) and nivolumab (N) as consolidation following autologous stem cell transplantation (ASCT) for high-risk hematologic malignancies - Cpit-001 trial. Blood. 2017;130(Supplement 1):340. doi:org/10.1182/blood.V130.Suppl_1.340.340
  89. 89. Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer. 2019;19(3):133-50. doi:10.1038/s41568-019-0116-x
  90. 90. Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel). 2020;12(3):738. doi:10.3390/cancers12030738
  91. 91. Boyiadzis MM, Kirkwood JM, Marshall JL, Pritchard CC, Azad NS, Gulley JL. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J Immunother Cancer. 2018;6(1):35. doi:10.1186/s40425-018-0342-x
  92. 92. Mateos M-V, Siegel D, Shah JJ, Reece D, Avigan D, Orlowski R, et al. Pembrolizumab (MK-3475) in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM)/ KEYNOTE-023. Journal for ImmunoTherapy of Cancer. 2015;3:160. doi:10.1186/2051-1426-3-S2-P160
  93. 93. Badros A, Hyjek E, Ma N, Lesokhin A, Dogan A, Rapoport AP, et al. Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017;130(10):1189-97. doi:10.1182/blood-2017-03-775122
  94. 94. Jelinek T, Paiva B, Hajek R. Update on PD-1/PD-L1 inhibitors in multiple myeloma. Front Immunol. 2018;9:2431. doi:10.3389/fimmu.2018.02431
  95. 95. Oriol A. A critical evaluation of pembrolizumab in addition to lenalidomide and dexamethasone for the treatment of multiple myeloma. Expert Rev Hematol. 2020;13(5):435-45. doi:10.1080/17474086.2020.1744432
  96. 96. Khan M, Arooj S, Wang H. NK cell-based immune checkpoint inhibition. Front Immunol. 2020;11:167. doi:10.3389/fimmu.2020.00167
  97. 97. Sun J, Muz B, Alhallak K, Markovic M, Gurley S, Wang Z, et al. Targeting CD47 as a novel immunotherapy for multiple myeloma. Cancers (Basel). 2020;12(2). doi:10.3390/cancers12020305
  98. 98. Lucas F, Pennell M, Huang Y, Benson DM, Efebera YA, Chaudhry M, et al. T-cell transcriptional profiling and immunophenotyping uncover LAG3 as a potential significant target of immune modulation in multiple myeloma. Biol Blood Marrow Transplant. 2019;26(1):7-15. doi:10.1016/j.bbmt.2019.08.009
  99. 99. Harjunpää H, Guillerey C. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 2020;200(2):108-19. doi:10.1111/cei.13407
  100. 100. Guillerey C, Harjunpää H, Carrié N, Kassem S, Teo T, Miles K, et al. TIGIT immune checkpoint blockade restores CD8(+) T-cell immunity against multiple myeloma. Blood. 2018;132(16):1689-94. doi:10.1182/blood-2018-01-825265
  101. 101. Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer. 2020;8(1). doi:10.1136/jitc-2020-000911
  102. 102. Nooka AK, Manteca MVM, Bahlis N, Weisel K, Oriol A, Alonso AA, et al. DREAMM-4: Evaluating safety and clinical activity of belantamab mafodotin in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma (MM). European Hematology Association EHA25; Virtual Congress, June 12, 2020.
  103. 103. Nishihori T, Kaufman JL, Hoffrnan JE, Blouch K, Pandit S, Butler E, et al. Open-label pilot study of genetically engineered NY-ESO-1 specific T cells (GSK3377794) alone or in combination with pembrolizumab in relapsed and refractory multiple myeloma. Biol Blood Marrow Transplant. 2020;26(3):S269-S70
  104. 104. Pirogova O, Darskaya E, Porunova V, Davidova E, Kudyasheva O, Bondarenko S, et al. Study of PD-1 inhibitor (nivolumab) with autologous hematopoietic stem cell transplantation in multiple myeloma patients. Bone Marrow Transplant. 2018;53:657-8
  105. 105. Cho HJ, Costa LJ, Davies FE, Neparidze N, Vij R, Feng YN, et al. Atezolizumab in combination with daratumumab with or without lenalidomide or pomalidomide: a phase Ib study in patients with multiple myeloma. Blood. 2018;132. doi:10.1182/blood-2018-99-114960
  106. 106. Cho HJ, Cole C, Martin TG, Zonder JA, Fay JW, Vij R, et al. A phase Ib study of atezolizumab (atezo) alone or in combination with lenalidomide or pomalidomide and/or daratumumab in patients (pts) with multiple myeloma (MM). J Clin Oncol. 2017;35(15):8053. doi:10.1200/JCO.2017.35.15_suppl. TPS8053
  107. 107. Fooksman DR, Mazumder A, McCarron M. CD138 regulates myeloma cell survival, proliferation, BM engraftment and tumor organization. Blood. 2015;126(23):2974. doi:org/10.1182/blood.V126.23.2974.2974
  108. 108. Jagannath S, Heffner LT, Jr., Ailawadhi S, Munshi NC, Zimmerman TM, Rosenblatt J, et al. Indatuximab ravtansine (BT062) monotherapy in patients with relapsed and/or refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2019;19(6):372-80. doi:10.1016/j.clml.2019.02.006
  109. 109. Yu TT, Xing LJ, Lin L, Liu JY, Wen K, Cho SF, et al. An immune based, anti-CD138 targeting antibody for the treatment of multiple myeloma. Blood. 2018;132. doi:10.1182/blood-2018-99-119112
  110. 110. Stein R, Mattes MJ, Cardillo TM, Hansen HJ, Chang CH, Burton J, et al. CD74: a new candidate target for the immunotherapy of B-cell neoplasms. Clin Cancer Res. 2007;13(18 Pt 2):5556s–63s. doi:10.1158/1078-0432.ccr-07-1167
  111. 111. Shah NN, Krishnan AY, Shah ND, Burke JM, Melear JM, Spira AI, et al. A Phase I open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies. Cancer Res. 2019;79(13). doi:10.1158/1538-7445.Am2019-ct104
  112. 112. Ailawadhi S, Kelly KR, Vescio RA, Jagannath S, Wolf J, Gharibo M, 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 Myeloma Leuk. 2018;19(1):29-34. doi:10.1016/j.clml.2018.08.018
  113. 113. Jelinek T, Hajek R. Monoclonal antibodies - A new era in the treatment of multiple myeloma. Blood Rev. 2016;30(2):101-10. doi:10.1016/j.blre.2015.08.004

Written By

Hanley N. Abramson

Submitted: July 22nd, 2020 Reviewed: September 25th, 2020 Published: October 30th, 2020