Abstract
Across all cancers, monoclonal antibodies have emerged as a potential strategy for cancer therapy. Monoclonal antibodies target antigens expressed on the surface of cancer cells and accessory cells. This targeted approach uses the host’s immune system to promote the killing of cancer cells. Multiple myeloma (MM) is the second most common hematologic malignancy that remains incurable in the majority of patients. The treatment of MM has evolved dramatically over the past decade and continues to evolve with the approval of four new drugs in 2015. Most recently the United States Food and Drug Administration (US FDA) approved two monoclonal antibodies for the treatment of this disease. Monoclonal antibodies are generally well-tolerated and offer a novel method of action for treated relapsed and refractory disease and are now being studied in the upfront setting. In this article, we review the evidence for the existing approved monoclonal antibodies and discuss promising targeted therapies and innovative strategies for the treatment of MM.
Introduction
Multiple myeloma (MM) is B-cell malignancy characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, production of a monoclonal protein present in the blood or urine and associated organ dysfunction. It is the second most common hematologic malignancy with approximately 30,330 cases diagnosed in the United States (US) annually [Siegel et al. 2016]. The past two decades have seen dramatic advances in the treatment of MM, beginning with the publication of a randomized trial investigating the use of high-dose melphalan and autologous stem cell transplant (SCT) in 1996 [Attal et al. 1996], followed by the introduction of the immunomodulatory (IMiD) drugs thalidomide [Singhal et al. 1999], lenalidomide (LEN) [Dimopoulos et al. 2007], and pomalidomide (POM), and the proteasome inhibitors (PI) bortezomib (BORT) [Richardson et al. 2003] and carfilzomib (CAR).
Despite these advances, MM remains an incurable malignancy in the majority of patients. Standard therapy today includes combination therapy with PIs and IMiDs. Patients with disease that is refractory to both PIs and IMiDs have poor prognoses with an estimated median survival of 9 months and an estimated event-free survival of 5 months [Kumar et al. 2012; Laubach et al. 2014]. Treatment of relapsed or refractory multiple myeloma (RRMM) presents a special therapeutic challenge, due to the heterogeneity of disease at relapse and the absence of clear biological-based recommendations regarding the choice of salvage therapies at various time points of disease progression. With increasing recognition of the inherent clonal heterogeneity and genomic instability of the plasma cells influencing both inherent and acquired therapeutic resistance, the identification of the optimal choice and sequence of therapies has become critical. There exists a critical unmet need for novel therapies in the setting of RRMM particularly in those patients that are refractory to both PIs and IMiDs. Recent advances in immunotherapy are now introducing another way to address this disease and potentially lead to the direction of cure.
Monoclonal antibodies designed to target cell surface proteins have emerged across all cancers as a potential strategy for targeted cancer therapy. There are a number of monoclonal antibodies that are routinely used in clinical practice and have transformed cancer care including, but not limited to, rituximab (CD20), trastuzumab (HER2), and nivolumab (NIVO, PD1). In 2015, two monoclonal antibodies were approved for the treatment of MM, daratumumab (DARA, CD38) and elotuzumab (SLAMF7). These are the first approved antibodies for the disease and reflect a paradigm shift towards the incorporation of immune therapy into MM care. Monoclonal antibodies are generally well-tolerated and associated with a favorable toxicity profile that is conducive to their incorporation into existing regimens. In this article, we will discuss the newly approved monoclonal antibodies and those that hold promise as well continue to look for new and innovative strategies for the treatment of MM.
CD38
CD38 is a type II transmembrane glycoprotein that is expressed in low levels on lymphoid and myeloid cells, and highly expressed on MM cells making it an attractive target for MM therapeutics. It is multifunctional and is involved with calcium flux and signal transduction in lymphoid and myeloid cells.
DARA is a human immunoglobulin (Ig)G1κ monoclonal antibody that targets CD38. In preclinical models, DARA was shown to elicit cell death through four mechanisms: antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP) and inhibition of the enzymatic activity of CD38 [de Weers et al. 2011; Overdijk et al. 2015; Lammerts van Bueren et al. 2014]. Recent data from Krejcik and colleagues, suggest novel mechanisms of action for DARA [Krejcik et al. 2016]. Their work demonstrates that treatment with DARA caused depletion of CD38+ immunosuppressive regulatory T and B-cells and myeloid-derived suppressor cells. This is associated with increase in T-helper cells, cytotoxic T-cells, T-cell functional response, and T-cell receptor clonality.
DARA received US Food and Drug Administration (FDA) approval in November 2015 based on single-agent efficacy demonstrated in two phase I/II trials [ClinicalTrials.gov identifiers: NCT00574288; NCT01985126] in patients with RRMM refractory to two or more prior lines of therapy. In part 1 of the NCT00574288 trial, the dose-escalation phase, DARA was administered at doses of 0.005–24 mg per kilogram of body weight [Lokhorst et al. 2015]. No maximum tolerated dose was identified. In part 2, the dose-expansion phase, 30 patients received 8 mg/kg of DARA and 42 received 16 mg/kg administered once weekly for 8 doses, twice monthly for 8 doses, and monthly for up to 24 months. In part 2, the median time since diagnosis was 5.7 years. Patients had a median of four prior lines of treatment. A total of 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to PIs and IMiDs, 64% had disease refractory to the combination of BORT and LEN, and 76% had received autologous SCT).
In terms of safety, a majority of patients experienced infusion-related reactions (IRRs) which were generally mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events (AEs). The most common AEs of grade 3 or 4 (in ⩾5% of patients) were pneumonia and thrombocytopenia. The overall response rate (ORR) was 36% in the cohort that received 16 mg per kilogram [15 patients had a partial response (PR) or better, including 2 with a complete response (CR) and 2 with a very good partial response (VGPR) and 10% in the cohort that received 8 mg per kilogram 3 had a PR]. In the cohort that received 16 mg per kilogram, the median progression-free survival (PFS) was 5.6 months [95% confidence interval (CI), 4.2–8.1], and 65% (95% CI, 28–86) of the patients who had a response did not have progression at 12 months.
These observations were corroborated in the NCT01985126 trials, also known as the SIRIUS trial, in a similar refractory MM population [Lonial et al. 2016]. In this study, patients received a median of five prior lines of therapy. All patients were refractory to their last line of therapy. IRRs (42.5%) were mainly grade 1/2 during the first infusion (grade 3 4.7%; no grade 4). No patients discontinued study due to IRRs; 5 (4.7%) discontinued treatment due to AEs. None of these AEs were assessed by the investigator to be DARA-related. The ORR was 29.2%, with 3 stringent complete responses (sCRs), 10 VGPRs, and 18 PRs with a 7.4-month median duration of response. Median time to progression was 3.7 months. Median overall survival had not been reached and the estimated 1-year overall survival rate was 65%. After a median follow up of 9.4 months, 14/31 (45.2%) of responders remained on therapy.
Based on these data, DARA was the first monoclonal antibody approved for the treatment of MM. The approval was for use as a single agent but current research is focused on identifying effective combinations of DARA with other potent MM therapeutics both in the RR setting and in the upfront setting. Phase III studies of LEN with dexamethasone (DEX) ± DARA [ClinicalTrials.gov identifier: NCT02076009] and BORT–DEX ± DARA [ClinicalTrials.gov identifier: NCT02136134] in patients with RRMM, and BORT–MEL–Prednisone (PRED) ± DARA [ClinicalTrials.gov identifier: NCT02195479] and LEN–DEX ± DARA [ClinicalTrials.gov identifier: NCT02252172] in newly diagnosed patients with MM are underway. The BORT–DEX ± DARA trial [ClinicalTrials.gov identifier: NCT02136134] also referred to as the Castor Trial, was presented at American Society of Clinical Oncology (ASCO) 2016 favoring the use of a triplet combination rather than BORT and DEX alone [Palumbo et al. 2016]. The 1-year PFS for the triplet was 60.7% versus 26.9% for BORT and DEX alone. The ORR was 83% with 19% achieving a CR and 59% achieving a VGPR or better. The POLLUX study comparing LEN–DEX alone with LEN–DEX–DARA, showed an 18-month PFS of 78% for the triplet versus 52% for the doublet. The ORR was 93% with 43% achieving a CR and 33% a VGPR [Dimopoulos et al. 2016]. As a result of these two studies, the US FDA has granted Breakthrough Therapy designation to DARA in combination with LEN–DEX or BORT–DEX for the treatment of MM patients who have received one prior line of therapy.
The administration of DARA has some unique but manageable challenges. DARA can cause severe infusion reaction. About one half of all patients experience a reaction, the majority during the first infusion. Nearly all reactions occur during the infusion or within 4 h of completing the infusion. Severe symptoms include bronchospasm, hypoxia, dyspnea, and hypertension. Patients require pre-medication with antihistamines, antipyretics, and corticosteroids. Corticosteroids are also administered to patients the first and second days following infusions to further reduce the risk of delayed infusion reactions. Another unique challenge is that DARA binds to CD38 on red blood cells resulting in a positive indirect antiglobulin test (Coombs test) which may persist up to 6 months. DARA bound to red blood cells masks the detection of antibodies to minor antigens in the patient’s serum. As such, it is necessary to type and screen patients prior to starting DARA and to notify the blood bank of this interference and that the patient is receiving DARA. Finally, as DARA is a human IgG κ monoclonal antibody, it can be detected on both serum protein electrophoresis and immunofixation assays which may obscure the ability to determine if a patient with IgG κ myeloma has had a CR.
Isatuximab (ISA) is another humanized IgG1 anti-CD38 monoclonal antibody that is undergoing clinical development. The two ongoing phase I/II dose-escalation studies are assessing ISA in patients with RRMM: as a monotherapy [ClinicalTrials.gov identifier: NCT01084252] or in combination with LEN and DEX [ClinicalTrials.gov identifier: NCT01749969].
In NCT01084252, patients who had received a median of 6.5 lines of prior therapy including BORT, CAR, LEN, and POM received single-agent ISA0.3–20 mg/kg every other week [Martin et al. 2014b]. The ORR was 24%, and 33% in patients who received the drug at doses of ⩾10 mg/kg. In the combination therapy study NCT01749969, patients with RRMM were treated with ISA at one of three dose levels (DLs) 3, 5 and 10 mg/kg, every 2 weeks, in combination with LEN and DEX [Martin et al. 2014a]. A total of 31 patients have been treated, including 24 patients (6 + 18) at the 10 mg/kg DL since the maximum tolerated dose (MTD) was not reached. The median time from initial MM diagnosis to first dose of ISA was 4.5 years (1.1–11.7) and the median number of prior treatment regimens was 6 (range 2–12). Over 95% of patients received prior IMiD therapy (LEN = 29, POM = 9) and >85% of these patients (27/31) were relapsed or refractory to at least one prior IMiD-based therapy. More than 90% of patients received BORT and 48% received prior CAR. No dose-limiting toxicities were reported. The most common treatment emergent AEs, regardless of relationship, included fatigue (41.9%), nausea (38.7%), upper respiratory tract infection (38.7%) and diarrhea (35.5%). IRRs occurred in 38.7% (n = 12) of patients, which predominantly occurred at cycle 1. Grade 3 IRRs occurred in two patients resulting in treatment discontinuation. The safety profile appears uniform across the DLs. With a median follow up of 6 months, the ORR (all treated patients) was 64.5% (sCR = 2, VGPR = 8, PR = 10) and clinical benefit response (CBR) was 71%. Patients relapsed and refractory to both IMiDs and PIs (n = 21) had an ORR of 52.4% and CBR of 61.9% [VGPR = 4, PR = 7, minimal response (MR) = 2]. Median PFS was 6.2 months.
MOR202 is a CD38 monoclonal antibody that induces ADCC and ADCP but does not induce CDC which is thought to be a major contributor to IRRs. Promising data have been reported from MOR202 alone or in combination with LEN or POM in RRMM [ClinicalTrials.gov identifier: NCT04121186] [Raab et al. 2016].
The results of these studies demonstrate the tolerability of monoclonal antibodies in combination with other treatments and the efficacy underscores the importance of ongoing research to identify the most potent combinations of therapies that include monoclonal antibodies and other effective therapies both in the relapses and upfront settings.
SLAMF7
Signaling lymphocyte activation molecule (SLAMF7), also known as CS1 (CD2-subset-1) is a cell surface glycoprotein that is highly expressed on both normal and MM plasma cells, and to a lower extent, on lymphocytes such as natural killer (NK) cells; it is absent in other tissues and hematopoietic stem cells [Hsi et al. 2008; Tai et al. 2008]. Expression of SLAMF7 is nearly universal in MM, irrespective of cytogenetic abnormalities and degree of disease progression.
Elotuzumab (ELO) is a humanized recombinant monoclonal IgG1 antibody targeting SLAMF7 that was also given US FDA approval in November 2015 in combination with LEN and DEX in patients with RRMM. ELO is proposed to have several modes of action including ADCC of MM cells involving NK cells and enhancement of NK cell activity against MM cells by binding to NK cell SLAMF7 [Collins et al. 2013].
In the phase I study of ELO as a single agent in patients with RRMM, ELO was not effective as monotherapy [Zonder et al. 2012]. The drug was generally well-tolerated but no objective responses were seen and approximately 75% of patients had progressive disease. However, when ELO is combined with LEN and DEX greater efficacy is seen. In the phase I/II trial in RRMM [ClinicalTrials.gov identifier: NCT00742560] ELO in combination with LEN and DEX showed an ORR of 84% [Lonial et al. 2013]. More recently, the phase III study, ELOQUENT-2 [ClinicalTrials.gov identifier: NCT01239797], compared the combination of ELO, LEN, and DEX to LEN and DEX in patients with RRMM [Lonial et al. 2015]. Patients with 1–3 prior lines of therapy were eligible to participate. Of note, the trial limited enrollment of patients with prior LEN treatment to 10%, and these patients had to demonstrate at least a PR to LEN. ELO 10 mg/kg was given weekly for the first two cycles and then every other week. LEN and DEX were given according to a conventional 28-day schedule. This trial enrolled 646 patients with a median of two prior lines of therapy. At a median follow up of 24.5 months, the rate of PFS at 1 year was superior in the ELO-containing group at 68% compared with 57% in the control group, and 41% versus 27% at 2 years, respectively. The median PFS in the ELO group was 19.4 months versus 14.9 months in the control group (p < 0.001). The ORR rate was also higher in the ELO group (79% versus 66%; p < 0.001). Common grade 3–4 AEs in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the ELO group and were grade 1–2 in 29 patients. Taken together, ELOQUENT-2 is the first study to show the benefit of adding a monoclonal antibody to conventional treatment in MM. Another study looked at BORT and DEX with or without ELO in RRMM patients treated with 1–3 prior therapies. A total of 152 patients were randomized. Median PFS for ELO-BORT-DEX (EBd) was 9.7 months versus 6.9 for BORT-DEX (Bd) [hazard ratio (HR) 0.71; 70% CI 0.58, 0.87; p = 0.08]. Grade 3 AEs (EBd, Bd): thrombocytopenia 7 (9%), 13 (17%); infections 14 (19%), 11 (15%). Infusion reactions (all grade 1–2, none at max 5 ml/min rate) occurred in 7% of patients with EBd [Jakubowiak et al. 2015].
There are ongoing studies assessing ELO in combination with LEN and DEX, and LEN, BORT, and DEX in the frontline setting for previously untreated MM. ELOQUENT-1 [ClinicalTrials.gov identifier: NCT01335399] is a phase III study of LEN and DEX with or without ELO in newly diagnosed MM (NDMM). SWOG 1211 [ClinicalTrials.gov identifier: NCT01668719] is a phase I/II study; patients with NDMM transplant-ineligible or transplant-deferred with high-risk disease were randomized to LEN–BORT–DEX versus LEN–BORT–DEX–ELO. There is an ongoing phase II study of LEN–BORT–DEX–ELO [ClinicalTrials.gov identifier: NCT02375555] in NDMM transplant-eligible and transplant-ineligible patients.
Other novel monoclonal antibodies under investigation
Programmed cell death protein 1 and programmed death-ligand
Programmed cell death protein (PD-1) is a type I transmembrane protein primarily expressed on activated T-cells, B-cells, myeloid cells, and antigen presenting cells (APCs) [Keir et al. 2008]. Binding of PD-1 to programmed death-ligand (PD-L) 1 and PD-L2 has been shown to inhibit T-cell activation [Freeman et al. 2000; Latchman et al. 2001]. In particular, PD-L1 has been shown to be upregulated on several cancers types including melanoma and non-small cell lung cancer and, in some cases, correlated with a negative prognosis [Konishi et al. 2004; Liu et al. 2007]. PD-1/PD-L interactions may also indirectly modulate the response to tumor antigens through T-cell/APC interactions. Therefore, PD-1 engagement may represent one means by which tumors evade immune surveillance and clearance [Topalian et al. 2012; Peng et al. 2012; Butte et al. 2007]. PD-1/PD-L1 signaling is dysregulated in patients with MM, with PD-L1 expressed on MM cells making it a potential and attractive target for immunotherapy in MM [Atanackovic et al. 2014].
NIVO was the first anti-PD-1 antibody that was investigated as monotherapy in the clinical setting for MM. In a phase I study that included patients with RR lymphoid malignancies, 27 patients with MM received NIVO [Lesokhin et al. 2016]. Drug-related AEs occurred in 52% of MM patients. Serious AEs included pneumonitis, myositis, and increased creatine phosphokinase occurring in 4% each. Only one patient was determined to have a CR after treatment of a rib plasmacytoma, otherwise, durable stable disease (SD) was seen. Subsequent trials have looked to combine PD-1 inhibition with established MM therapies.
Pembrolizumab (PEM) is a humanized IgG4 monoclonal antibody against PD-1. It directly blocks the interaction between PD-1 and PD-L1/PD-L2. The rationale for combining PD-1 inhibition with IMiDs was that IMiDs reduce PD-L1 and PD-1 expression on MM cells and T-cells and myeloid-derived suppressor cells and that IMiDs enhance checkpoint blockade-induced effector cytokine production in MM bone marrow and induced cytotoxicity against MM cells [Gorgun et al. 2015]. In the phase I study of PEM in combination with LEN and DEX [San Miguel et al. 2015; Mateos et al. 2016b] 51 patients were enrolled with a median of 72% having ⩾3 prior lines of therapy. A total of 76% of patients were refractory to LEN. The ORR was 75% (24% VGPR, 53% PR). Of the LEN refractory patients, ORR was 50% (13% VGPR, 35% PR). A total of 94% of patients experienced AEs, most commonly neutropenia, thrombocytopenia, and diarrhea. Overall, 65% were grade 3–5. This was consistent with individual drug safety profiles for approved indications. Similar results were seen in the phase I of PEM in combination with POM and DEX with ORR of 60% [Badros et al. 2015]. Notable AEs in this study also included neutropenia, anemia, and thrombocytopenia, as well, as pneumonia and pneumonitis.
Combination therapy with PD-1 inhibitors appears to be tolerable and a promising area of investigation in efforts to engage the power of the immune system in MM therapy.
B-cell activating factor
B-cell activating factor (BAFF) is a type II transmembrane protein and member of the tumor necrosis factor (TNF) family. It is produced in the bone marrow and is expressed by monocytes, macrophage, dendritic cells, and some T-cells and binds to three receptors of the TNF receptor family, B-cell maturation antigen (BCMA), and BAFF receptor (BAFF-R), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). BAFF-R is expressed on MM cells and serum BAFF levels are increased in MM patients compared with healthy donors [Neri et al. 2007]. The bone marrow microenvironment is the main source of BAFF for MM cells. BAFF is an important survival factor for B-cells and can promote the generation of plasmablasts from activated memory B-cells by enhancing their survival [Avery et al. 2003].
Tabalumab (TAB), a human monoclonal antibody that neutralizes membrane-bound and soluble BAFF, has demonstrated both anti-myeloma activity and osteoclastogenesis inhibition in xenograft models of MM. A phase I study combined TAB with BORT in patients with previously treated MM who were not refractory to BORT [Raje et al. 2012]. A total of 48 patients were enrolled who had received a median of three prior lines of therapy. Grade 3–4 toxicities occurring in two or more patients included peripheral sensory neuropathy, pneumonia, thrombocytopenia, neutropenia, diarrhea, musculoskeletal pain, acute renal failure, fatigue, anemia, neuralgia, and gastrointestinal hemorrhage. The ORR was 46%. Confirmed responses included 2 CRs, 4 VGPRs, and 16 PRs. A three-arm study [ClinicalTrials.gov identifier: NCT01602224] randomizing patients to the combinations of BORT, DEX, and TAB 100 mg versus TAB 300 mg versus placebo has been completed but not yet reported.
CD138
CD138 (syndecan-1) is a transmembrane heparan sulphate bearing proteoglycan, expressed during plasma cell stage of B-cell maturation, that can bind to type I collagen inducing expression of metalloproteinases, and promoting bone resorption and invasion [Ridley et al. 1993]. Further, CD138 can be shed in the extracellular matrix, trapping growth-promoting and proangiogenic cytokines [Borset et al. 2000; Dhodapkar et al. 1998]. CD138 is highly overexpressed in various solid tumors and hematological malignancies, and is highly specific for plasmacytic differentiation within the spectrum of hematologic malignancy because it is absent on highly proliferative normal plasmablasts and all earlier B-cell stages [O’Connell et al. 2004]. Increased soluble CD138 levels correlate with MM tumor burden and poor outcomes [Dhodapkar et al. 1997]. For these reasons, CD138 is an interesting target for MM therapy.
Indatuximab ravtansine (INDA) is an antibody drug conjugate (ADC), comprising the anti-CD138 chimerized monoclonal antibody (nBT062) and the maytansinoid DM4 as a cytotoxic agent. It is designed to bind to CD138 on cancer cells, and then release DM4 after internalization to cause cell death [Kelly et al. 2014]. As a single agent, INDA showed acceptable tolerability and evidence of activity in RRMM [Heffner et al. 2012]. About 90% of the reported AEs were grades 1–2. The most frequently reported AEs were anemia, diarrhea, and fatigue. Among the 23 patients evaluable for efficacy, one patient achieved a PR. SD for at least 3 months was noted in an additional 11 patients, with median PFS of 112 (90–245) days. Thus disease control (PR + SD) was noted in >50% (12/23) of patients. Preclinical data suggested increased efficacy of INDA in combination with LEN and DEX which was the rationale for the phase II study of INDA in combination with LEN and DEX [Kelly et al. 2014]. The median number of prior lines of therapy was 3 and 73% of patients had had prior LEN exposure. At the presented interim analysis, the most common reported AEs were diarrhea, fatigue, nausea, and hypokalemia. Among the 36 patients across all DLs currently evaluable for efficacy, the ORR is 78%; including 1 sCR, 2 CRs, 10 VGPRs, and 15 PRs.
B-cell maturation antigen
BCMA (CD269) is a member of the TNF receptor superfamily, TNFRSF17 [Ryan et al. 2007]. Expression of BCMA is restricted to the B-cell lineage where it is predominantly expressed in the interfollicular region of germinal centers [Chiu et al. 2007] and on differentiated plasma cells [O’Connor et al. 2004] and plasmablasts. [Avery et al. 2003] BCMA is virtually absent on naïve and memory B-cells [Novak et al. 2004; Jelinek and Darce 2005] but it is selectively induced during plasma cell differentiation where it may support humoral immunity by promoting the survival of normal plasma cells and plasmablasts. Multiple independent analyses of mRNA in human MM samples indicate that all patients’ samples have high levels of BCMA [Tai et al. 2006; Moreaux et al. 2004] making it a very attractive therapeutic target. BCMA is also a receptor for BAFF and a proliferation-inducing ligand (APRIL). Upon binding to its ligand BAFF and APRIL, the survival of bone marrow (BM) plasma cells and plasmablasts is promoted [Belnoue et al. 2008]. These results define an active BAFF/APRIL/BCMA axis in the pathophysiology of MM and define it as a target of interest [Tai et al. 2014].
AMG 224 is an ADC comprised of anti-BCMA–MCC–DM1; where anti-BCMA is an anti-human BCMA IgG1 antibody; MCC is the noncleavable linker 4-(N-maleimidomethyl) cyclohexane-1-carboxylate conjugated to lysine residues in the antibody; and DM1 is a semi-synthetic derivative of the ansamycin antibiotic maytansine conjugated to MCC. There is an ongoing phase I study of AMG 224 in RRMM [ClinicalTrials.gov identifier: NCT02561962]. Similarly, GSK2857916 is a humanized IgG1 (ADC) which binds specifically to BCMA that is being investigated in the phase I setting [ClinicalTrials.gov identifier: NCT02064387]. The parent anti-BCMA antibody (J6M0) is conjugated to the microtubule inhibitor monomethyl auristatin-F (MMAF) via a protease resistant maleimidocaproyl (mc) linker to produce the GSK2857916 ADC molecule. Preclinical data show that GSK2857916 specifically blocks cell growth via G2/M arrest and induces caspase 3-dependent apoptosis in MM cells, alone and in co-culture with BM stromal cells or various effector cells. It strongly inhibits colony formation by MM cells while sparing surrounding BCMA-negative normal cells. Furthermore, GSK2857916 recruits macrophages and mediates ADCP of MM cells [Tai et al. 2014]. GSK2857916 appears to have anti-MM activity through multiple mechanisms and is another promising immunotherapy in MM.
Bispecific T-cell engagers
Bispecific T-cell engagers (BiTEs) are comprised of two single-chain variable fragments, one that binds to CD3 molecules on T-cells and the other to a surface antigen on the target cells [Lutterbuese et al. 2010]. Regular IgG1 antibodies cannot engage T-cells because they lack the Fc receptors. BiTEs are able to elicit cytotoxicity without requiring the APC, major histocompatibility complex (MHC)-I/peptide complex, and co-stimulatory molecules needed for regular T-cell response. Blinatumomab, a CD19/CD3 bispecific BiTE antibody has been US FDA-approved for the treatment of acute lymphoblastic leukemia based on high response rates in the relapsed or refractory setting [Topp et al. 2015]. MM cell-specific BiTEs are in development and offer yet another approach to treating the disease. For example, BI836909 is a novel BiTE that binds to BCMA and CD3 that has shown preclinical activity both in vitro and in vivo [Hipp et al. 2015]. In vitro, BI 836909 induced dose-dependent redirected lysis of human MM cell lines. In vivo, anti-tumor activity of BI 836909 was assessed in NOD/SCID mice reconstituted with human T-cells and bearing subcutaneous or orthotopic xenografts derived from human MM cell lines. Statistically significant dose-dependent anti-tumor activity was observed at doses of 50 µg/kg/day and higher. In an orthotopic L-363 xenograft model, treatment with BI 836909 resulted in a statistically significant prolonged survival at doses of 5 µg/kg/day and higher. There is currently an ongoing phase I dose-escalation study of BI 836909 monotherapy in last line MM patients [ClinicalTrials.gov identifier: NCT02514239] [Hipp et al. 2015].
Rank ligand
Perturbations in the balance between bone formation and resorption can lead to generalized osteoporosis (resulting from estrogen deficiency and aging) or local bone lysis (resulting from rheumatoid arthritis and bone metastases). The Receptor Activator of Nuclear Factor Kappa-B (RANK) and Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) system has been identified as an essential mediator of osteoclast (OCL) precursors to stimulate or promote differentiation into OCLs and activate mature OCLs to resorb bone [Teitelbaum and Ross, 2003]. Therefore, RANKL is a therapeutic target for diseases associated with increased bone resorption.
Denosumab is a fully human monoclonal IgG2 antibody to RANKL that binds with high affinity (Kd 3 × 10–12 m) and specificity to the soluble and cell membrane-bound forms of human RANKL. Denosumab is highly specific because it binds only to RANKL and not to other members of the TNF family, including TNFα, TNFβ, TNF-related apoptosis-inducing ligand, or CD40 ligand [Elliott et al. 2006]. Denosumab binding prevents the activation of RANK and inhibits the formation, activation, and survival of OCLs. As a consequence, bone resorption and cancer-induced bone destruction are reduced.
Study 20050134 was a proof-of-concept, single-arm study to investigate if RANKL inhibition with denosumab could reduce serum M-protein levels in relapsed or plateau-phase MM patients [Vij et al. 2009]. Results of this study demonstrated that no patients in either cohort met the protocol-defined objective response criteria of CR or PR, but that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates.
Study 20050244 is a phase III study in patients with advanced cancers including solid tumors (excluding breast and prostate), lymphoma or MM and radiographic evidence of at least one bone metastasis (or lytic bone lesion from MM) [Henry et al. 2011]. A total of 180 of 1140 patients enrolled had a diagnosis of MM. This study demonstrated that denosumab delayed the time to first on-study skeletal related event (SRE) such as pathologic fracture, radiation therapy or surgery to bone, or spinal cord compression, and was noninferior to zoledronic acid (HR: 0.84; 95% CI: 0.71–0.98; p = 0.0007). Although numerically greater, time to first on-study SRE (p = 0.03 unadjusted; p = 0.06 adjusted for multiplicity) and time to first and subsequent SRE (rate ratio: 0.90; 95% CI: 0.77–1.04; p = 0.14) with denosumab were not superior to zoledronic acid [Henry et al. 2011]. An ad hoc analysis examining overall survival for the three stratification variables (non-small cell lung cancer, MM, and other solid tumors) demonstrated a HR (95% CI) of 0.79 (0.65, 0.95) for non-small cell lung cancer (n = 702), 2.26 (1.13, 4.50) for MM (n = 180), and 1.08 (0.90, 1.30, n = 894) for ‘other’ solid tumors. For MM, imbalances in baseline disease characteristics, SCT therapy, and withdrawals due to consent withdrawn or lost to follow up favored zoledronic acid. These baseline and on-study imbalances may partially account for the difference observed between treatment groups. To definitively address the discrepancies, there is currently a phase III, randomized, double-blind, multicenter study comparing denosumab with zoledronic acid in treatment of bone disease in newly diagnosed MM patients [ClinicalTrials.gov identifier: NCT01345019]. The current US FDA-approved label for denosumab does not include MM.
It is estimated that 25–50% of patients with MM present with renal insufficiency and approximately 9% require hemodialysis [Knudsen et al. 1994]. There is no current standard of care with respect to bone-targeted therapy in this patient population. Bisphosphonates are renally cleared and are considered contraindicated in oncology patients with a creatinine clearance <30 ml/min. Denosumab is not cleared by the kidneys. As a result, there is no restriction in its use in renal insufficiency. There exists an unmet need for bone-targeted in MM patients with renal insufficiency. A single-arm study of denosumab in MM patients with renal insufficiency (CrCl < 30) [ClinicalTrials.gov identifier: NCT02833610] is currently underway to address this unmet need.
Conclusion
Monoclonal antibodies offer a new avenue by which we can approach MM therapy. They provide an approach which is independent of the genetic heterogeneity and genetic risk in our patients. To date, the antibodies that have been evaluated for our disease have been well-tolerated and some have demonstrated single-agent efficacy. Because of the favorable toxicity profile, monoclonal antibodies can be combined with other treatments such as IMiDs and PIs to create effective new therapies. Existing data support the use of IMiDs in combination with antibodies both in terms of efficacy and tolerability.
We are only at the beginning of our understanding of the role of monoclonal antibodies in MM treatment. There are many questions that remain. Important questions that lie ahead include which sequence to use approved antibodies, can more than one antibody be included in a regimen, will the introduction of monoclonal antibodies in the upfront setting increase depth and duration of response or possibly cure patients, and finally is there a role for monoclonal antibodies in the precursor disease states monoclonal gammopathy of undetermined significance and smoldering myeloma? Many of these questions are starting to be addressed in ongoing clinical trials. There are single-agent trials of both DARA and ELO in patients with smoldering myeloma underway. Monoclonal antibodies have been transformative for a number of recalcitrant cancers and there is reason for great optimism that we too can make use of targeted therapy in our fight against MM (Table 1).
Monoclonal antibody-based treatment in MM.
BAFF, B-cell activating factor; BORT, bortezomib; CR, complete response; DARA, daratumumab; DEX, dexamethasone; ELO, elotuzumab; INDA, indatuximab ravtansine; ISA, isatuximab; LEN, lenalidomide; MM, multiple myeloma; NIVO, nivolumab; ORR, overall response rate; PD-1, programmed cell death protein; PD-L1, programmed death-ligand 1; PEM, pembrolizumab; POM, pomalidomide; PR, partial response; PRED, prednisone; TAB, tabalumab; THAL, thalidomide; VGPR, very good partial response.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare that there is no conflict of interest.