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Monoclonal antibody therapy in multiple myeloma: where do we stand and where are we going?
Multiple myeloma is a plasma cell malignancy that is characterized by refractory and relapsing course of disease. Despite the introduction of high-dose chemotherapy in combination with autologous stem cell transplantation and innovative agents such as proteasome inhibitors and immunomodulatory drugs, achieving cure in multiple myeloma is a challenging endeavor. In the last couple of years, enormous advances were made in implementing monoclonal antibody therapy in multiple myeloma. A large number of preclinical and clinical studies have been introduced successfully, demonstrating a safe and efficient administration of monoclonal antibodies in multiple myeloma. In particular, the application of monoclonal antibodies in combination with immunomodulatory drugs, proteasome inhibitors, corticosteroids or conventional chemotherapy seem to be promising and will expand the treatment arsenal for patients with multiple myeloma. First draft submitted: 1 September 2015; Accepted for publication: 3 December 2015; Published online: 18 February 2016 Keywords: immunotherapy • monoclonal antibodies • multiple myeloma • targeted therapy
Multiple myeloma (MM) is a hematologic B-cell malignancy that is characterized by clonal proliferation of plasma cells in the bone marrow, production of increased amount of monoclonal immunoglobulins and associated end-organ damage [1] . The main clinical features of this fatal disease are recurrent infections, kidney failure, hypercalcemia, impairment of hematopoiesis and bone destruction [2] . The introduction of high-dose chemotherapy and autologous stem cell transplantation has revolutionized the treatment of patients with MM [3] . Hereafter, the implementation of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) led to further improvement of clinical outcome [4,5] . Despite the expansion of the treatment options for MM over the last couple of years, achieving cure in patients with MM, especially with high-risk features, is a challenging goal, as refractory and relapsing course of disease
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is the rule rather than the exception. Furthermore, a large number of patients do not qualify for high-dose chemotherapy and stem cell transplantation due to comorbidities and advanced age. It is also important to point out the disadvantages and profound side effects of novel agents, which include peripheral neuropathy, impairment of hematopoiesis with immunosuppression, venous thromboembolism and diarrhea. In search of more efficient treatment approach with better tolerability, more efforts have been made implementing targeted therapy for MM. The application of monoclonal antibodies (mAbs) has been already introduced successfully in other cancer types in the last couple of years. In contrast to conventional, nonspecific chemotherapy, the main advantage of mAb treatment is the highly specific and targeted approach of destroying tumor cells while being relatively well-tolerated by applying
Immunotherapy (Epub ahead of print)
Sharmilan Thanendrarajan1, Faith E Davies1, Gareth J Morgan1, Carolina Schinke1, Pankaj Mathur1, Christoph J Heuck1, Maurizio Zangari1, Joshua Epstein1, Shmuel Yaccoby1, Niels Weinhold1, Bart Barlogie2 & Frits van Rhee*,1 Myeloma Institute, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA 2 Tisch Cancer Institute, Mount Sinai Hospital, 1470 Madison Avenue, New York, NY 10029, USA *Author for correspondence: Tel.: +1 501 414 2873 Fax: +1 501 526 2273 vanrheefrits@ uams.edu 1
part of
ISSN 1750-743X
Review Thanendrarajan, Davies, Morgan et al. humanized or fully human mAbs. A wide range of cellular and noncellular antigens have been specified as targets for mAb therapy in cancer treatment, for example, VEGFR, EGFR, HER2 and B-lymphocyte antigen CD20 [6] . These targets are mainly involved in proliferation and cell viability, cell-to-cell communication, antiapoptotic pathways, angiogenesis and interaction between cancer cells and microenvironment and generation of antitumor immune response [7,8] . Monoclonal antibodies directly impair signal transduction and generate signal arrest by specifically binding or eliminating essential cell-surface antigen and inducing modulation of the receptor or interfering with ligand binding and dimerization of the receptor leading to blockage of activation signals necessary for cell growth and survival (Figure 1) [8] . mAbs can be also used as targeted carriers of cytotoxic agents to convey intracellular toxins or radioactive isotopes, which may directly destroy tumor cells or activate prodrugs specifically within the tumor [8,9] . The ADCC and complement-dependent cytotoxicity (CDC) are the most important effects of mAb therapy, which are mainly depending on Fcbased mechanism and involvement of immune effector cells [6,7] . The ADCC is based on activating Fc receptors on myeloid and natural killer (NK) cells by tumor cell-attached immunoglobulins and subsequent cytotoxicity through perforin and granzymes release or involvement of death ligands, Fas ligand and TNF-related apoptosis-inducing ligand (Figure 1) [7] . In contrast, the CDC process is mediated by interaction between Fc domains and complement activating proteins with consequent induction of the membrane attack complexes leading to cell destruction and death (Figure 1) [7] . Moreover, the production of cytokines, chemokines and opsonins through ADCC and CDC enhances the development of T-cell immunity [7] . In general, mAbs stimulate the cross-priming of T cells through endocytosis and phagocytosis of antigen-containing immune complexes and antibodyopsonized tumor cells, and promote antigen presentation and internalization of antigen-presenting cells, respectively [7] . In the last couple of years, more and more insights on potential targets in MM have been discovered and specified, including signaling molecules, cell surface proteins, plasma cell growth factors and mediators of adhesion [7,9–10] . In our paper, we mainly focus on clinical trials that have demonstrated beneficiary effects in MM (Tables 1 & 2) . Our main goal is to provide a comprehensive overview and summary of innovative and pioneering strategies in application of mAb treatment in MM (Figure 2) .
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Immunotherapy (Epub ahead of print)
Targeting myeloma cells directly Elotuzumab
Recently van Rhee et al. reported about the cell surface glycoprotein CS1 (CD subset 1, SLAMF7) that is expressed in large quantities on myeloma cells while having limited expression in other tissue cells [24] . Elotuzumab is a humanized mAb that activates NK cell function and consequently leading to ADCC through upregulation of IL-2 and TNF-α pathway by targeting the CS1 glycoprotein [25,26] . It also activates directly CS1-bearing NK cells and inhibits CS1-mediated interaction between MM cells and bone marrow stroma cells (BMSCs) [27] . A multicenter open-label, dose escalation Phase I trial including 35 highly pretreated patients with refractory and relapsing MM (RRMM) demonstrated that the solitary administration of elotuzumab with dosage of 0.5–20 mg/kg intravenous (iv.) every 2 weeks for maximum of 8 or 16 weeks, respectively, was generally well-tolerated and attained stable disease (SD) in 26.5% (n = 9) of all the patients [11] . The most common adverse events were mild to moderate (grade 1–2) in severity and included fever and chills, headache cough and back pain [11] . In vitro and in vivo studies have shown that administration of elotuzumab in combination with the PI bortezomib (BTZ) revealed synergistic effects regarding antimyeloma activity [24] . Jakubowiak et al. recently published data on a Phase I clinical trial, which included the application of elotuzumab in combination with BTZ in 28 patients with a median of two prior therapies [12] . Elotuzumab and BTZ were infused intravenously in a dose of 2.5, 5.0, 10 or 20 mg on days 1 and 11, and 1.3 mg/m2 on days 1, 4, 8 and 11, respectively, in 21-day cycles in a classic dose-escalating design. After four cycles, patients with at least SD were eligible to resume treatment until disease progression (PD) or excruciating toxicity. A partial response (PR) rate or better was noted in 48% (n = 13) of the patients, and interestingly, two out of three patients (67%) were even refractory to BTZ. The median time to progression (TTP) was specified with 9.5 months. The most frequent grade 3 to 4 adverse events were lymphopenia (25%), fatigue (14%), peripheral neuropathy (11%) and pneumonia (11%). Overall, the authors described the combined application of BTZ and elotuzumab as safe and promising for further clinical trials [12] . Another promising Phase 1 study was recently conducted by using elotuzumab in combination with lenalidomide (LEN) and dexamethasone in 29 patients with advanced MM and a median of three prior therapies. Elotuzumab was administered intravenously with 5.0, 10, 20 mg/kg on days 1, 8, 15 and 22 of a 28-day cycle in the first two cycles, and day 1 and 15 each subsequent cycle, LEN orally with
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Monoclonal antibody therapy in multiple myeloma
Review
Monoclonal antibodies
NK cells Myeloid cells
Complement activating proteins
Receptor 1
3
Membrane attack complex
Perforins Granzymes
Fc receptor
MAC
2
CDC
ADCC Apoptosis
Figure 1. Effect of monoclonal antibodies in antimyeloma treatment. CDC: Complement-dependent cytotoxicity, MAC: Membrane attack complex.
25 mg on days 1–21 of a 28-day cycle and dexamethasone 40 mg orally weekly. Objective responses were obtained in 82% (complete remission [CR]: n = 1, very good partial remission [VGPR]: n = 8, PR: n = 14) of treated patients and at least three patients achieved SD. The median TTP was not reached after a median of 16.4 months follow-up for patients in the 20 mg/kg cohort who were treated until PD. The most frequent grade 3 to 4 toxicities were neutropenia (36%), thrombocytopenia (21%), diarrhea (11%) and fatigue (11%). Only two patients experienced a serious infusion reaction, in terms of anaphylactic reaction (grade 4) and stridor (grade 3) during the first treatment cycle [13] . In the ELOQUENT-2 trial, Lonial et al. confirmed these findings in a larger amount of patients with relapsed and refractory MM: 321 patients received elotuzumab plus LEN and dexamethasone and 325 patients (control) only LEN plus dexamethasone. After a follow-up of 24.5 months, the authors came to conclusion that the elotuzumab arm reduced the risk of PD or death by 30%. In detail, the ORR was 79 versus 66% (p < 0.001), and progression-free survival (PFS) 19.4 versus 14.9 months (HR: 0.7; 95% CI: 0.57–0.85; p < 0.001) in favor of elotuzumab. The most common adverse events in both arms were lymphocytopenia, neutropenia, fatigue and pneumonia [14] . On the basis of this study the US Federal Drug and Food Administration (FDA) has approved in November 2015 the application of elotuzumab in combination with lenalidomide and dexamethasone for the treatment of patients with refractory and relapsing multiple myeloma who have received one to three prior therapies.
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Daratumumab & other anti-CD38 mAbs
CD38 is a type II transmembrane glycoprotein, which is markedly expressed in B lymphocytes and other cells from the immune system. It is involved in apoptosis, cell activation, differentiation and proliferation [28] . In particular, CD38 participates in B lymphocyte activation and regulation in plasma cells by phosphorylation of substrates, intracellular calcium release and increased expression of molecules involved in proliferation or apoptosis [28,29] . In vitro studies support the fact that daratumumab (DAR) is highly efficient in inducing CDC and ADCC in MM and patient-derived cell lines, both with autologous and allogeneic effector cells [28,29] . Moreover, it generates antibody-dependent cellular phagocytosis by macrophages, and induces apoptosis upon secondary cross-linking and modulates CD38 enzymatic function [28,29] . Daratumumab at low dosing has already proven to be active in vivo xenograft models by demonstrating interruption of tumor growth [28] . van de Veer et al. have proven that DAR in combination with LEN and/ or BTZ increased MM cells lysis in vivo by more than twofold in both combinations [30,31] . In particular, the combination of LEN, BTZ and DAR exhibited the highest MM cell lysis. Notably, MM cells from LEN/ BTZ-resistant patients revealed significantly higher than expected levels of cell lysis with additional treatment of DAR, indicating antimyeloma efficacy, despite the development of drug resistance [30,31] . Nijhof et al. demonstrated that the application of LEN accelerated the DAR-mediated MM cell lysis through activation of NK cells ex vivo, and reduced tumor growth
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Immunotherapy (Epub ahead of print)
RRMM (Phase I)
ELO + LEN + DEX (n = 29)
DARA monotherapy
RRMM (Phase I)
DZB monotherapy (n = 44)
DZB 4–12 mg/kg iv., 1 week (uniform weekly/ dose escalating schedule)
Lymphopenia, fatigue, peripheral neuropathy and pneumonia
ORR (8 mg/kg): 10% (PR: n = 3), ORR (16 mg/kg): 36% (PR: n = 15; VGPR: n = 2, CR: n = 2)
SD: 20% (n = 9)
Fatigue, headache, nausea, anemia
Fatigue (n = 42, 40%) and anemia (n = 35, 33%)
Pneumonia, thrombocytopenia (>grade 3 adverse events)
Lymphocytopenia, neutropenia, fatigue and pneumonia
ORR: 82% (CR: n = 1, VGPR: n = Neutropenia, 8, PR: n = 14), TTP: 16.4 months thrombocytopenia, (ELO: 20 mg/kg) diarrhea and fatigue
PR: 48% (n = 13), TTP: 9.5 months
Fever, chills, headache, cough and back pain
SD: 26.5% (n = 9)
DARA 16 mg/kg IV weekly for 8 weeks (cycle 1 ORR: 29%, median response + 2) every 2 weeks for 16 weeks (cycle 3 – 6), duration: 7.4 months, PFS: 3.7 every 4 weeks (cycle 7 and higher) months, 12-months OS: 64.8%
DARA 8 mg/kg (n = 30) or 16 mg/kg (n = 42), 1 week for 8 cycles, 2 m for 8 cycles, monthly for 24 months
Adverse events
10 mg/kg iv., days 1, 8, 15 and 22 (two cycles), ORR: 79 vs 66%, PFS: 19.4 vs day 1 and 15 (with three cycles)+ LEN 25 mg 14.9 months, reduction of risk PO day 1–21, + DEX 40 mg PO weekly of PD or death: 30%
5.0, 10, 20 mg/kg iv., day 1, 8, 15 and 22 (two cycles), day 1 and 15 (with three cycles) + LEN 25 mg PO day 1–21 + DEX 40 mg PO weekly, in 28-day cycle
2.5, 5, 10 or 20 mg/kg iv., day 1 and 11 + BTZ 1.3 mg/m², day 1, 4, 11, 14, in 28-day cycles, four cycles and more
ELO 0.5–20 mg/kg iv., every 2 weeks, 8–16 weeks
Response rate
Application
[16]
[35]
[15]
[14]
[13]
[12]
[11]
Ref.
BTZ: Bortezomib; CBR: Clinical benefit rate; CFZ: Carfilzomib; CR: Complete remission; C/W: Continue with; DARA: Daratumumab; DEX: Dexamethasone; DZB: Dacetuzumab; EFS: Event-free survival; ELO: Elotuzumab; HD: High dose; LCT: Lucatumumab; LEN: Lenalidomide; MEL: Melphalan; MTZ: Milatuzumab; NMM: Newly diagnosed multiple myeloma; ORR: Overall response rate; PD: Progressive disease; PFS: Progression-free survival; PO: Per os (oral); POM: Pomalidomide; PR: Partial remission; PRED: Prednisone; RRMM: Refractory and relapsing MM; SD: Stable disease; THAL: Thalidomide; TTP: Time to progression; VGPR: Very good partial remission.
Dacetuzumab
CD40
DARA monotherapy (n = 106)
RRMM (Phase II)
Daratumumab
RRMM (Phase I, II)
CD38
RRMM (Phase III)
ELO + BTZ (n = 28)
ELO + LEN + DEX (n = 321) vs LEN + DEX (n = 325)
RRMM (Phase I)
ELO monotherapy (n = 35)
RRMM (Phase I)
Elotuzumab
CS-1 (SLAMF7)
Indication
Monoclonal antibody/ combination
Target
Table 1. Targeting the myeloma cells directly by using monoclonal antibodies in Phase I, II and III clinical trials.
Review Thanendrarajan, Davies, Morgan et al.
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ORR: none Nausea, fever, fatigue SD: 26% (n = 5/19, for and chills (12%: >grade 3 >3 months; n = 1/19, 17 months) adverse events) MZB monotherapy (n = 26)
MTZ 1.5, 4, 8, 16 mg/kg iv., 2 weeks, 4 weeks
RRMM (Phase I/II)
Milatuzumab CD74
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BTZ: Bortezomib; CBR: Clinical benefit rate; CFZ: Carfilzomib; CR: Complete remission; C/W: Continue with; DARA: Daratumumab; DEX: Dexamethasone; DZB: Dacetuzumab; EFS: Event-free survival; ELO: Elotuzumab; HD: High dose; LCT: Lucatumumab; LEN: Lenalidomide; MEL: Melphalan; MTZ: Milatuzumab; NMM: Newly diagnosed multiple myeloma; ORR: Overall response rate; PD: Progressive disease; PFS: Progression-free survival; PO: Per os (oral); POM: Pomalidomide; PR: Partial remission; PRED: Prednisone; RRMM: Refractory and relapsing MM; SD: Stable disease; THAL: Thalidomide; TTP: Time to progression; VGPR: Very good partial remission.
[18]
[17]
Anemia, chills, fever and hypercalcemia LCT monotherapy (n = 28)
LCT 1, 3, 4.5, 6 mg/kg iv., 1 or 2 administration SD: n = 12 (43%) PR (>8 in 1 week, 4 weeks, (n = 28) months): n = 1 (4%)
RRMM (Phase I)
Lucatumumab CD40 (cont.)
Adverse events Response rate
Application
Indication
Monoclonal antibody/ combination
Target
Table 1. Targeting the myeloma cells directly by using monoclonal antibodies in Phase I, II and III clinical trials (cont.).
Ref.
Monoclonal antibody therapy in multiple myeloma
Review
of MM cells from LEN and bortezomib-refractory patients in an in vivo xenograft model [32] . Furthermore, DAR significantly increased response rate by increasing MM cell lysis in other triple immunochemotherapy regimen (LEN–BTZ–DEX; MEL–PRED [Prednisone]–BTZ) [32] . The same Dutch research group brought to attention that all-trans retinoic acid improved MM cell lysis by upregulation of the CD 38 expression and reduced expression of the complementinhibitory proteins CD55 and CD59 [33] . Moreover, they realized that the DAR-mediated lysis of primary MM cells is synergistically improved by blocking of NK cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of NK cells with the IMiD LEN, respectively [34] . Most recently, Lokhost et al. published data on application of DAR as single agent in highly pretreated RRMM in a Phase I/II trial. The patients either received 8 mg/ kg DAR (n = 30) or 16 mg/kg (n = 42) once weekly for eight cycles, twice monthly for eight cycles and monthly for 24 months. The ORR was 10% in the 8 mg/kg arm with three patients achieving PR, and 36% in the cohort that received 16 mg/kg with 15 patients reaching PR (CR: n = 2, VGPR: n = 2). The median PFS was 5.6 months in the 16 mg/kg arm (95% CI: 4.2–8.1), and those patients who expressed response to treatment with DAR event had a PFS of >12 months. Overall, the authors pointed out that DAR is a safe and efficient treatment option for patients with highly pretreated, relapsing and refractory MM [15] . The US FDA has approved DAR as first mAb for treatment of patients with refractory and relapsing multiple myeloma who have received at least three prior lines of therapy, including a PI and an IMiD agent, or who are double-refractory. Daratumumab administration was recommended at a dose of 16 mg/kg once every week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks until disease progression. The approval is based on the above mentioned study from Lokhorst et al. and a multicenter, open-label study evaluating response rates in 106 patients with RRMM treated with DAR as single agent. The ORR was 29% (95% CI: 21–39%) with a median response duration of 7.4 months (range: 1.2 to >13.1 months), PFS of 3.7 months (95% CI 2.8–4.6) and 12-months OS of 64.8% (95% CI 51.2–75.5) [35] . The results of a large number of planned and ongoing Phase I and II clinical trials using DAR either as single agent or in combination with PI, IMiDs, melphalan and/or steroids in smoldering, untreated, newly diagnosed and refractory and/or relapsing myeloma stage are eagerly awaited in the near future (Table 3) . Other promising anti-CD38 mAbs that target distinct epitopes on CD38 other than DAR are already
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Immunotherapy (Epub ahead of print)
Siltuximab
MM/castleman disease/BNHL (Phase I)
STX monotherapy (n = 67)
RRMM (Phase II)
STX + DEX (n = 39) vs STX monotherapy (n = 14)
BHQ880 (Anti-DKK-1)
RRMM (Phase IB)
Anti-DKK-1 antibody monotherapy (n = 28)
IPH2101 (Anti-KIR)
RRMM (Phase I)
IPH 2101 (Anti-KIR) + LEN (n = 15)
Bevacizumab
RRMM (Phase II)
BVZ (n = 6) vs BVZ + THAL (n = 6)
IL-6
DKK-1
KIR
VEGF
ORR (single STX): none ORR (STX + DEX): 23% (PR: 17%, MR: 6%)/47 TTP (STX + DEX): 4.4 months PFS (STX + DEX): 3.7 months OS (STX + DEX): 20.4 months
CR: n = 2 (15%)/13
Response rate
BVZ 10 mg/kg iv. every 2 weeks THAL 100 mg daily with dose escalation by 100 mg per week up to 400 mg daily for 8 weeks
Anti-KIR antibody: 0.2 mg/kg or 1 mg/kg or 2 mg/kg iv. on day 1 + LEN 10 mg/25 mg, days 1–21/28 days
BVZ + THAL: PR: n = 2 (224 and 369 days), SD: n = 3 BVZ: only SD and PD, shorter period of TTF
ORR: n = 5 (33.3%), VGPR: n = 2, PR: n = 3, MR: n = 1, SD: n = 6
Anti-DKK-1 antibody (3–40 mg/kg) Trend toward increase of bone + antimyeloma agents + zolendronic mineral density and bone strength acid (hip and spine) in anti-DKK-1 arm
STX 6 mg/kg iv., day 1 + 15/28 days + DEX 40 mg days 1–4, days 9–12, days 17–20/28 days (DEX was added to single agent STX if PD or 8 months in one patient (4%). The authors conclude that further studies are necessary to evaluate the beneficiary of lucatumumab in combination with other established antimyeloma agents, such as IMiDs and PIs [17] . Milatuzumab
CD74 is an essential chaperone of the MHC class II membrane protein family, which is preferentially involved in antigen presentation for immune response and initiating survival pathways and B-cell proliferation [44,45] . It exhibits high expression on malignant B cells and limited expression on normal tissue cells, qualifying CD74 as a potential therapeutic target in B-NHL lymphoma and MM [46] . In several clinical trials milatuzumab has already been successfully applied in patients with relapsed or refractory B-NHL, either as single agent or in combination with other drugs [47,48] . In vitro studies have already demonstrated that milatuzumab in combination with doxorubicin, BTZ or dexamethasone exhibits synergistic antimyeloma effects with increased apoptosis and growth inhibition rate [46] . In xenograft mouse models with disseminated MM, milatuzumab in combination with BTZ significantly prolonged survival rate [46] . In a Phase I dose-escalating trial, milatuzumab was applied as single agent in refractory and relapsing myeloma patients. In detail, 25 highly pretreated patients with only short response rates to prior treatment regimen received milatuzumab doses of 1.5, 4.0, 8.0 or 16.0 mg/kg administered twice
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10.2217/imt.15.118
Review Thanendrarajan, Davies, Morgan et al.
Targeted therapy Myeloma cells
Targets CS1 (SLAMF7) CD38 CD40 CD74 CD20
Monoclonal antibodies Elotuzumab Daratumumab Dacetuzumab Lucatumumab Milatuzumab Rituximab
Microenvironment
Targets IL-6 BAFF RANK-L DKK-1 KIR VEGF
Monoclonal antibodies Siltuximab Tabalumab Denosumab Anti-DKK-1 (BHQ880) Anti-KIR (IPH2101) Bevcizumab
Figure 2. Targeted therapy in multiple myeloma: overview of potential targets and monoclonal antibodies.
weekly for 4 weeks. Although no objective response was noted, at least 26% (n = 5) of the 19 patients who have completed the treatment expressed SD for at least 3 months, and even one patient remained in SD for 17 months. Taking the heavily pretreated and refractory patient population in consideration, milatuzumab seems to have the predicate to become a potent antimyeloma drug in combination with other agents (Table 3) [18] . Targeting the microenvironment Siltuximab
It is well-known that IL-6 weakens the antimyeloma efficacy of glucocorticoids, and promotes proliferation and drug resistance of MM cells [49,50] . In preclinical in vitro studies with human myeloma cell lines, Voorhees et al. have provided clear evidence that the antiIL-6 mAb siltuximab (CNTO 328) enhanced the cytotoxic activity of dexamethasone. This property was applicable for BTZ- and glucocorticoid-resistant human myeloma cell lines, and was preserved in the presence of human BMSCs. A clear, synergistic antimyeloma effect was noted in the combined application of dexamethasone and siltuximab, and addition of BTZ further improved the cytotoxic activity of this combination [49] . Moreover, Hunsucker and colleagues demonstrated that siltuximab synergistically accelerated the cytotoxicity of melphalan in human myeloma cell lines [50] . In a Phase I clinical trial with application of single agent siltuximab in patients with B-NHL, MM and Castleman disease, the authors came to conclusion that no dose-related or cumulative toxicities
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Immunotherapy (Epub ahead of print)
were standing out across all disease indications, and a dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease [19] . In a Phase II, multicenter clinical study siltuximab was utilized alone (n = 14) or in combination with dexamethasone (n = 39) in patients with RRMM with more than two prior treatments, including BTZbased regimen [20] . Siltuximab as single agent did not show any response, but in combination with dexamethasone it achieved a response rate of 23% (17%: PR, 6%: MR), including efficacy in dexamethasonerefractory disease. The median TTP was 4.4, PFS was 3.7 and OS was 20.4 months in the combination therapy arm, respectively. Overall, infectious problems were frequently noted, in terms of upper respiratory infections (14%), pneumonia, oral candidiasis and cellulitis (8% each). Hematological toxicities were also often noted, but manageable in total [20] . More and more clinical trials are conducted in which siltuximab is incorporated in earlier phases of the disease and in combination with IMiDs and PI, for example, in high-risk smoldering and newly diagnosed myeloma patients (Table 3) . Tabalumab
Survival of plasma cells in MM cells is mainly depending on interaction between malignant plasma cells and the bone marrow microenvironment. A very essential part of this microenvironment is the B-cell activating factor (BAFF), which belongs to the group of B-lymphocyte stimulators [51] . It is highly produced by osteoclasts and mesenchymal stroma cells and binds to
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NMM and ineligible for HD-chemo (Phase III)
DARA + BTZ + MEL + PRED vs BTZ + MEL + PRED
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NA
NCT02195479
NCT02316106
Ref.
NCT01998971
NCT02252172
BTZ: Bortezomib; CBR: Clinical benefit rate; CFZ: Carfilzomib; CR: Complete remission; C/W: Continue with; DARA: Daratumumab; DEN: Denosumab; DEX: Dexamethasone; DKK-1: Dickkopf-1; DZB: Dacetuzumab; EFS: Event-free survival; HD: High dose; iv.: Intravenous; LEN: Lenalidomide; MM: Multiple myeloma; MEL: Melphalan; NMM: Newly diagnosed MM; ORR: Overall response rate; PCB: Placebo; PD: Progressive disease; POM: Pomalidomide; PR: Partial remission; PRED: Prednisone; RRMM: Refractory and relapsing MM; SD: Stable disease; SMM: Smoldering multiple myeloma; STX: Siltuximab; TABA: Tabalumab; THAL: Thalidomide; TTP: Time to progression; VGPR: Very good partial remission.
+ BTZ + MEL + PRED + BTZ + THAL + DEX + POM + DEX + CFZ + DEX + CFZ + LEN + DEX
+ BTZ + DEX
NMM or RRMM (Phase I) DARA
+ DEX 40 mg iv. or PO, once a week for a maximum of 2 years or until disease progression or unacceptable toxicity, whichever comes first vs Same as above without DAR
DARA 16 mg/kg iv., 1 × weekly for 8 weeks, then 1 × every other week for 16 weeks, then 1 × every 4 weeks until PD, unacceptable toxicity or end of study (maximum up to 5 years) + LEN 25 mg PO days 1–21 of each 28-day cycle, for a maximum of 2 years or until disease progression or unacceptable toxicity, whichever comes first.
DAR + LEN + DEX vs LEN + DEX
+ PRED 60 mg/m2, PO, 1 × daily, on days 1–4 (cycle 1–9) vs Same as above without DARA
BTZ 1.3 mg/m2 SC, 2 × w, in weeks 1, 2, 4 and 5 (cycle 1), 1 × week in weeks 1, 2, 4 and 5 (cycles 2–9), + MEL 9 mg/m2 PO, 1 × daily,
DARA 16 mg/kg iv., 1 × weekly, for 6 weeks (cycle 1), every 3 weeks (cycle 2–9), every 4 weeks (until PD or unacceptable toxicity or study end)
vs 16 mg/kg IV, 1 × week (cycle 1), 1 cycle = 8 weeks
NMM and ineligible for HD-chemo (Phase III)
DARA monotherapy
DARA 16 mg/kg iv., 1 × weekly (cycle 1), every other week (cycle 2 + 3) every 4 weeks from cycle 4 to 7, every 8 weeks from cycle 8 to 20, 1 cycle = 8 weeks vs 16 mg/kg iv., 1 × week in cycle 1, very 8 weeks (cycle 2–20)
Daratumumab
Smoldering MM (Phase II)
Application
CD38
Indication monoclonal antibody/ combination
Target
Table 3. Application of monoclonal antibodies in treatment of multiple myeloma in ongoing Phase I, II and III clinical trial listed on www.clinicaltrials.gov.
Monoclonal antibody therapy in multiple myeloma
Review
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RRMM (Phase II)
CD38 (cont.)
Immunotherapy (Epub ahead of print)
RRMM (Phase Ib)
SAR + BTZ + CYC + DEX
SAR + POM + DEX
SAR (escalating dose) day 1, 8, 15, 22 (1st cycle), then day 1 and 15 + POM 4 mg days 1–21/28 days + DEX 40 mg day 1, 8, 15, 22 in 28 days cycle
SAR (escalating dose) days 1, 8, 15, 22 and 29 (1st cycle), then days 1 and 15 (subsequent cycles) + BTZ 1.3 mg/m2 SC days 1, 4, 8, 11, 22, 25, 29, 32 (1st cycle), then weekly days 1, 8, 15, 22 (cycle 2–12) + CYC 300 mg/m2 PO days 1, 8, 22, 29 (1st cycle), then days 1, 8, 15 (cycle 2–12) + DEX 20 mg PO/iv. days 1, 4, 8, 11, 15, 22, 25, 29, 32 (1st cycle), then if patients 75 years: DEX 20 mg days 1, 8, 15, 22 + maintenance (after cycle 12): SAR (at initial assigned dose) + DEX 20 mg once every 28 days
SAR (escalating dose) days 1, 8, 15, 22/28 days (1st cycle) days 1 and 15/28 days every other cycle
SAR 5 mg/kg or 10 mg/kg day 1 and 15/28 days + CFZ 20–27 mg/m2 (in standard application)
SAR (escalating dose) day 1 and 15 (every cycle) or day 1, 8, 15 and 22 (1st cycle) + day 1 and 15 every other cycle + LEN 25 mg PO days 1–21/28 days + DEX 40 mg PO day 1, 8, 15, 22/28 days
DAR 16 mg/kg iv., 1 w (cycle 1–3), 3 w (cycle 4–9), 4 w (>cycle 10) + BTZ 1.3 mg/m2 SC days 1, 4, 8 and 11 /21 days (8 cycles) + DEX 20 mg, days 1, 2, 4, 5, 8, 9, 11 and 12 (8 cycles) 1 cycle = 21 days vs same as above without DAR
DAR 16 mg/kg iv: 1 × w (cycles 1 + 2), 1 × 2 w (cycles 3 + 6); once only (on day 1) during treatment cycles seven onward. + LEN 25 mg PO days 1–21/28 days + DEX 40 mg 1 × w (20 mg, w, >75 years or BMI
Monoclonal antibody therapy in multiple myeloma: where do we stand and where are we going?
Multiple myeloma is a plasma cell malignancy that is characterized by refractory and relapsing course of disease. Despite the introduction of high-dose chemotherapy in combination with autologous stem cell transplantation and innovative agents such as proteasome inhibitors and immunomodulatory drugs, achieving cure in multiple myeloma is a challenging endeavor. In the last couple of years, enormous advances were made in implementing monoclonal antibody therapy in multiple myeloma. A large number of preclinical and clinical studies have been introduced successfully, demonstrating a safe and efficient administration of monoclonal antibodies in multiple myeloma. In particular, the application of monoclonal antibodies in combination with immunomodulatory drugs, proteasome inhibitors, corticosteroids or conventional chemotherapy seem to be promising and will expand the treatment arsenal for patients with multiple myeloma. First draft submitted: 1 September 2015; Accepted for publication: 3 December 2015; Published online: 18 February 2016 Keywords: immunotherapy • monoclonal antibodies • multiple myeloma • targeted therapy
Multiple myeloma (MM) is a hematologic B-cell malignancy that is characterized by clonal proliferation of plasma cells in the bone marrow, production of increased amount of monoclonal immunoglobulins and associated end-organ damage [1] . The main clinical features of this fatal disease are recurrent infections, kidney failure, hypercalcemia, impairment of hematopoiesis and bone destruction [2] . The introduction of high-dose chemotherapy and autologous stem cell transplantation has revolutionized the treatment of patients with MM [3] . Hereafter, the implementation of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) led to further improvement of clinical outcome [4,5] . Despite the expansion of the treatment options for MM over the last couple of years, achieving cure in patients with MM, especially with high-risk features, is a challenging goal, as refractory and relapsing course of disease
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is the rule rather than the exception. Furthermore, a large number of patients do not qualify for high-dose chemotherapy and stem cell transplantation due to comorbidities and advanced age. It is also important to point out the disadvantages and profound side effects of novel agents, which include peripheral neuropathy, impairment of hematopoiesis with immunosuppression, venous thromboembolism and diarrhea. In search of more efficient treatment approach with better tolerability, more efforts have been made implementing targeted therapy for MM. The application of monoclonal antibodies (mAbs) has been already introduced successfully in other cancer types in the last couple of years. In contrast to conventional, nonspecific chemotherapy, the main advantage of mAb treatment is the highly specific and targeted approach of destroying tumor cells while being relatively well-tolerated by applying
Immunotherapy (Epub ahead of print)
Sharmilan Thanendrarajan1, Faith E Davies1, Gareth J Morgan1, Carolina Schinke1, Pankaj Mathur1, Christoph J Heuck1, Maurizio Zangari1, Joshua Epstein1, Shmuel Yaccoby1, Niels Weinhold1, Bart Barlogie2 & Frits van Rhee*,1 Myeloma Institute, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA 2 Tisch Cancer Institute, Mount Sinai Hospital, 1470 Madison Avenue, New York, NY 10029, USA *Author for correspondence: Tel.: +1 501 414 2873 Fax: +1 501 526 2273 vanrheefrits@ uams.edu 1
part of
ISSN 1750-743X
Review Thanendrarajan, Davies, Morgan et al. humanized or fully human mAbs. A wide range of cellular and noncellular antigens have been specified as targets for mAb therapy in cancer treatment, for example, VEGFR, EGFR, HER2 and B-lymphocyte antigen CD20 [6] . These targets are mainly involved in proliferation and cell viability, cell-to-cell communication, antiapoptotic pathways, angiogenesis and interaction between cancer cells and microenvironment and generation of antitumor immune response [7,8] . Monoclonal antibodies directly impair signal transduction and generate signal arrest by specifically binding or eliminating essential cell-surface antigen and inducing modulation of the receptor or interfering with ligand binding and dimerization of the receptor leading to blockage of activation signals necessary for cell growth and survival (Figure 1) [8] . mAbs can be also used as targeted carriers of cytotoxic agents to convey intracellular toxins or radioactive isotopes, which may directly destroy tumor cells or activate prodrugs specifically within the tumor [8,9] . The ADCC and complement-dependent cytotoxicity (CDC) are the most important effects of mAb therapy, which are mainly depending on Fcbased mechanism and involvement of immune effector cells [6,7] . The ADCC is based on activating Fc receptors on myeloid and natural killer (NK) cells by tumor cell-attached immunoglobulins and subsequent cytotoxicity through perforin and granzymes release or involvement of death ligands, Fas ligand and TNF-related apoptosis-inducing ligand (Figure 1) [7] . In contrast, the CDC process is mediated by interaction between Fc domains and complement activating proteins with consequent induction of the membrane attack complexes leading to cell destruction and death (Figure 1) [7] . Moreover, the production of cytokines, chemokines and opsonins through ADCC and CDC enhances the development of T-cell immunity [7] . In general, mAbs stimulate the cross-priming of T cells through endocytosis and phagocytosis of antigen-containing immune complexes and antibodyopsonized tumor cells, and promote antigen presentation and internalization of antigen-presenting cells, respectively [7] . In the last couple of years, more and more insights on potential targets in MM have been discovered and specified, including signaling molecules, cell surface proteins, plasma cell growth factors and mediators of adhesion [7,9–10] . In our paper, we mainly focus on clinical trials that have demonstrated beneficiary effects in MM (Tables 1 & 2) . Our main goal is to provide a comprehensive overview and summary of innovative and pioneering strategies in application of mAb treatment in MM (Figure 2) .
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Immunotherapy (Epub ahead of print)
Targeting myeloma cells directly Elotuzumab
Recently van Rhee et al. reported about the cell surface glycoprotein CS1 (CD subset 1, SLAMF7) that is expressed in large quantities on myeloma cells while having limited expression in other tissue cells [24] . Elotuzumab is a humanized mAb that activates NK cell function and consequently leading to ADCC through upregulation of IL-2 and TNF-α pathway by targeting the CS1 glycoprotein [25,26] . It also activates directly CS1-bearing NK cells and inhibits CS1-mediated interaction between MM cells and bone marrow stroma cells (BMSCs) [27] . A multicenter open-label, dose escalation Phase I trial including 35 highly pretreated patients with refractory and relapsing MM (RRMM) demonstrated that the solitary administration of elotuzumab with dosage of 0.5–20 mg/kg intravenous (iv.) every 2 weeks for maximum of 8 or 16 weeks, respectively, was generally well-tolerated and attained stable disease (SD) in 26.5% (n = 9) of all the patients [11] . The most common adverse events were mild to moderate (grade 1–2) in severity and included fever and chills, headache cough and back pain [11] . In vitro and in vivo studies have shown that administration of elotuzumab in combination with the PI bortezomib (BTZ) revealed synergistic effects regarding antimyeloma activity [24] . Jakubowiak et al. recently published data on a Phase I clinical trial, which included the application of elotuzumab in combination with BTZ in 28 patients with a median of two prior therapies [12] . Elotuzumab and BTZ were infused intravenously in a dose of 2.5, 5.0, 10 or 20 mg on days 1 and 11, and 1.3 mg/m2 on days 1, 4, 8 and 11, respectively, in 21-day cycles in a classic dose-escalating design. After four cycles, patients with at least SD were eligible to resume treatment until disease progression (PD) or excruciating toxicity. A partial response (PR) rate or better was noted in 48% (n = 13) of the patients, and interestingly, two out of three patients (67%) were even refractory to BTZ. The median time to progression (TTP) was specified with 9.5 months. The most frequent grade 3 to 4 adverse events were lymphopenia (25%), fatigue (14%), peripheral neuropathy (11%) and pneumonia (11%). Overall, the authors described the combined application of BTZ and elotuzumab as safe and promising for further clinical trials [12] . Another promising Phase 1 study was recently conducted by using elotuzumab in combination with lenalidomide (LEN) and dexamethasone in 29 patients with advanced MM and a median of three prior therapies. Elotuzumab was administered intravenously with 5.0, 10, 20 mg/kg on days 1, 8, 15 and 22 of a 28-day cycle in the first two cycles, and day 1 and 15 each subsequent cycle, LEN orally with
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Monoclonal antibody therapy in multiple myeloma
Review
Monoclonal antibodies
NK cells Myeloid cells
Complement activating proteins
Receptor 1
3
Membrane attack complex
Perforins Granzymes
Fc receptor
MAC
2
CDC
ADCC Apoptosis
Figure 1. Effect of monoclonal antibodies in antimyeloma treatment. CDC: Complement-dependent cytotoxicity, MAC: Membrane attack complex.
25 mg on days 1–21 of a 28-day cycle and dexamethasone 40 mg orally weekly. Objective responses were obtained in 82% (complete remission [CR]: n = 1, very good partial remission [VGPR]: n = 8, PR: n = 14) of treated patients and at least three patients achieved SD. The median TTP was not reached after a median of 16.4 months follow-up for patients in the 20 mg/kg cohort who were treated until PD. The most frequent grade 3 to 4 toxicities were neutropenia (36%), thrombocytopenia (21%), diarrhea (11%) and fatigue (11%). Only two patients experienced a serious infusion reaction, in terms of anaphylactic reaction (grade 4) and stridor (grade 3) during the first treatment cycle [13] . In the ELOQUENT-2 trial, Lonial et al. confirmed these findings in a larger amount of patients with relapsed and refractory MM: 321 patients received elotuzumab plus LEN and dexamethasone and 325 patients (control) only LEN plus dexamethasone. After a follow-up of 24.5 months, the authors came to conclusion that the elotuzumab arm reduced the risk of PD or death by 30%. In detail, the ORR was 79 versus 66% (p < 0.001), and progression-free survival (PFS) 19.4 versus 14.9 months (HR: 0.7; 95% CI: 0.57–0.85; p < 0.001) in favor of elotuzumab. The most common adverse events in both arms were lymphocytopenia, neutropenia, fatigue and pneumonia [14] . On the basis of this study the US Federal Drug and Food Administration (FDA) has approved in November 2015 the application of elotuzumab in combination with lenalidomide and dexamethasone for the treatment of patients with refractory and relapsing multiple myeloma who have received one to three prior therapies.
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Daratumumab & other anti-CD38 mAbs
CD38 is a type II transmembrane glycoprotein, which is markedly expressed in B lymphocytes and other cells from the immune system. It is involved in apoptosis, cell activation, differentiation and proliferation [28] . In particular, CD38 participates in B lymphocyte activation and regulation in plasma cells by phosphorylation of substrates, intracellular calcium release and increased expression of molecules involved in proliferation or apoptosis [28,29] . In vitro studies support the fact that daratumumab (DAR) is highly efficient in inducing CDC and ADCC in MM and patient-derived cell lines, both with autologous and allogeneic effector cells [28,29] . Moreover, it generates antibody-dependent cellular phagocytosis by macrophages, and induces apoptosis upon secondary cross-linking and modulates CD38 enzymatic function [28,29] . Daratumumab at low dosing has already proven to be active in vivo xenograft models by demonstrating interruption of tumor growth [28] . van de Veer et al. have proven that DAR in combination with LEN and/ or BTZ increased MM cells lysis in vivo by more than twofold in both combinations [30,31] . In particular, the combination of LEN, BTZ and DAR exhibited the highest MM cell lysis. Notably, MM cells from LEN/ BTZ-resistant patients revealed significantly higher than expected levels of cell lysis with additional treatment of DAR, indicating antimyeloma efficacy, despite the development of drug resistance [30,31] . Nijhof et al. demonstrated that the application of LEN accelerated the DAR-mediated MM cell lysis through activation of NK cells ex vivo, and reduced tumor growth
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Immunotherapy (Epub ahead of print)
RRMM (Phase I)
ELO + LEN + DEX (n = 29)
DARA monotherapy
RRMM (Phase I)
DZB monotherapy (n = 44)
DZB 4–12 mg/kg iv., 1 week (uniform weekly/ dose escalating schedule)
Lymphopenia, fatigue, peripheral neuropathy and pneumonia
ORR (8 mg/kg): 10% (PR: n = 3), ORR (16 mg/kg): 36% (PR: n = 15; VGPR: n = 2, CR: n = 2)
SD: 20% (n = 9)
Fatigue, headache, nausea, anemia
Fatigue (n = 42, 40%) and anemia (n = 35, 33%)
Pneumonia, thrombocytopenia (>grade 3 adverse events)
Lymphocytopenia, neutropenia, fatigue and pneumonia
ORR: 82% (CR: n = 1, VGPR: n = Neutropenia, 8, PR: n = 14), TTP: 16.4 months thrombocytopenia, (ELO: 20 mg/kg) diarrhea and fatigue
PR: 48% (n = 13), TTP: 9.5 months
Fever, chills, headache, cough and back pain
SD: 26.5% (n = 9)
DARA 16 mg/kg IV weekly for 8 weeks (cycle 1 ORR: 29%, median response + 2) every 2 weeks for 16 weeks (cycle 3 – 6), duration: 7.4 months, PFS: 3.7 every 4 weeks (cycle 7 and higher) months, 12-months OS: 64.8%
DARA 8 mg/kg (n = 30) or 16 mg/kg (n = 42), 1 week for 8 cycles, 2 m for 8 cycles, monthly for 24 months
Adverse events
10 mg/kg iv., days 1, 8, 15 and 22 (two cycles), ORR: 79 vs 66%, PFS: 19.4 vs day 1 and 15 (with three cycles)+ LEN 25 mg 14.9 months, reduction of risk PO day 1–21, + DEX 40 mg PO weekly of PD or death: 30%
5.0, 10, 20 mg/kg iv., day 1, 8, 15 and 22 (two cycles), day 1 and 15 (with three cycles) + LEN 25 mg PO day 1–21 + DEX 40 mg PO weekly, in 28-day cycle
2.5, 5, 10 or 20 mg/kg iv., day 1 and 11 + BTZ 1.3 mg/m², day 1, 4, 11, 14, in 28-day cycles, four cycles and more
ELO 0.5–20 mg/kg iv., every 2 weeks, 8–16 weeks
Response rate
Application
[16]
[35]
[15]
[14]
[13]
[12]
[11]
Ref.
BTZ: Bortezomib; CBR: Clinical benefit rate; CFZ: Carfilzomib; CR: Complete remission; C/W: Continue with; DARA: Daratumumab; DEX: Dexamethasone; DZB: Dacetuzumab; EFS: Event-free survival; ELO: Elotuzumab; HD: High dose; LCT: Lucatumumab; LEN: Lenalidomide; MEL: Melphalan; MTZ: Milatuzumab; NMM: Newly diagnosed multiple myeloma; ORR: Overall response rate; PD: Progressive disease; PFS: Progression-free survival; PO: Per os (oral); POM: Pomalidomide; PR: Partial remission; PRED: Prednisone; RRMM: Refractory and relapsing MM; SD: Stable disease; THAL: Thalidomide; TTP: Time to progression; VGPR: Very good partial remission.
Dacetuzumab
CD40
DARA monotherapy (n = 106)
RRMM (Phase II)
Daratumumab
RRMM (Phase I, II)
CD38
RRMM (Phase III)
ELO + BTZ (n = 28)
ELO + LEN + DEX (n = 321) vs LEN + DEX (n = 325)
RRMM (Phase I)
ELO monotherapy (n = 35)
RRMM (Phase I)
Elotuzumab
CS-1 (SLAMF7)
Indication
Monoclonal antibody/ combination
Target
Table 1. Targeting the myeloma cells directly by using monoclonal antibodies in Phase I, II and III clinical trials.
Review Thanendrarajan, Davies, Morgan et al.
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ORR: none Nausea, fever, fatigue SD: 26% (n = 5/19, for and chills (12%: >grade 3 >3 months; n = 1/19, 17 months) adverse events) MZB monotherapy (n = 26)
MTZ 1.5, 4, 8, 16 mg/kg iv., 2 weeks, 4 weeks
RRMM (Phase I/II)
Milatuzumab CD74
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BTZ: Bortezomib; CBR: Clinical benefit rate; CFZ: Carfilzomib; CR: Complete remission; C/W: Continue with; DARA: Daratumumab; DEX: Dexamethasone; DZB: Dacetuzumab; EFS: Event-free survival; ELO: Elotuzumab; HD: High dose; LCT: Lucatumumab; LEN: Lenalidomide; MEL: Melphalan; MTZ: Milatuzumab; NMM: Newly diagnosed multiple myeloma; ORR: Overall response rate; PD: Progressive disease; PFS: Progression-free survival; PO: Per os (oral); POM: Pomalidomide; PR: Partial remission; PRED: Prednisone; RRMM: Refractory and relapsing MM; SD: Stable disease; THAL: Thalidomide; TTP: Time to progression; VGPR: Very good partial remission.
[18]
[17]
Anemia, chills, fever and hypercalcemia LCT monotherapy (n = 28)
LCT 1, 3, 4.5, 6 mg/kg iv., 1 or 2 administration SD: n = 12 (43%) PR (>8 in 1 week, 4 weeks, (n = 28) months): n = 1 (4%)
RRMM (Phase I)
Lucatumumab CD40 (cont.)
Adverse events Response rate
Application
Indication
Monoclonal antibody/ combination
Target
Table 1. Targeting the myeloma cells directly by using monoclonal antibodies in Phase I, II and III clinical trials (cont.).
Ref.
Monoclonal antibody therapy in multiple myeloma
Review
of MM cells from LEN and bortezomib-refractory patients in an in vivo xenograft model [32] . Furthermore, DAR significantly increased response rate by increasing MM cell lysis in other triple immunochemotherapy regimen (LEN–BTZ–DEX; MEL–PRED [Prednisone]–BTZ) [32] . The same Dutch research group brought to attention that all-trans retinoic acid improved MM cell lysis by upregulation of the CD 38 expression and reduced expression of the complementinhibitory proteins CD55 and CD59 [33] . Moreover, they realized that the DAR-mediated lysis of primary MM cells is synergistically improved by blocking of NK cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of NK cells with the IMiD LEN, respectively [34] . Most recently, Lokhost et al. published data on application of DAR as single agent in highly pretreated RRMM in a Phase I/II trial. The patients either received 8 mg/ kg DAR (n = 30) or 16 mg/kg (n = 42) once weekly for eight cycles, twice monthly for eight cycles and monthly for 24 months. The ORR was 10% in the 8 mg/kg arm with three patients achieving PR, and 36% in the cohort that received 16 mg/kg with 15 patients reaching PR (CR: n = 2, VGPR: n = 2). The median PFS was 5.6 months in the 16 mg/kg arm (95% CI: 4.2–8.1), and those patients who expressed response to treatment with DAR event had a PFS of >12 months. Overall, the authors pointed out that DAR is a safe and efficient treatment option for patients with highly pretreated, relapsing and refractory MM [15] . The US FDA has approved DAR as first mAb for treatment of patients with refractory and relapsing multiple myeloma who have received at least three prior lines of therapy, including a PI and an IMiD agent, or who are double-refractory. Daratumumab administration was recommended at a dose of 16 mg/kg once every week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks until disease progression. The approval is based on the above mentioned study from Lokhorst et al. and a multicenter, open-label study evaluating response rates in 106 patients with RRMM treated with DAR as single agent. The ORR was 29% (95% CI: 21–39%) with a median response duration of 7.4 months (range: 1.2 to >13.1 months), PFS of 3.7 months (95% CI 2.8–4.6) and 12-months OS of 64.8% (95% CI 51.2–75.5) [35] . The results of a large number of planned and ongoing Phase I and II clinical trials using DAR either as single agent or in combination with PI, IMiDs, melphalan and/or steroids in smoldering, untreated, newly diagnosed and refractory and/or relapsing myeloma stage are eagerly awaited in the near future (Table 3) . Other promising anti-CD38 mAbs that target distinct epitopes on CD38 other than DAR are already
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Immunotherapy (Epub ahead of print)
Siltuximab
MM/castleman disease/BNHL (Phase I)
STX monotherapy (n = 67)
RRMM (Phase II)
STX + DEX (n = 39) vs STX monotherapy (n = 14)
BHQ880 (Anti-DKK-1)
RRMM (Phase IB)
Anti-DKK-1 antibody monotherapy (n = 28)
IPH2101 (Anti-KIR)
RRMM (Phase I)
IPH 2101 (Anti-KIR) + LEN (n = 15)
Bevacizumab
RRMM (Phase II)
BVZ (n = 6) vs BVZ + THAL (n = 6)
IL-6
DKK-1
KIR
VEGF
ORR (single STX): none ORR (STX + DEX): 23% (PR: 17%, MR: 6%)/47 TTP (STX + DEX): 4.4 months PFS (STX + DEX): 3.7 months OS (STX + DEX): 20.4 months
CR: n = 2 (15%)/13
Response rate
BVZ 10 mg/kg iv. every 2 weeks THAL 100 mg daily with dose escalation by 100 mg per week up to 400 mg daily for 8 weeks
Anti-KIR antibody: 0.2 mg/kg or 1 mg/kg or 2 mg/kg iv. on day 1 + LEN 10 mg/25 mg, days 1–21/28 days
BVZ + THAL: PR: n = 2 (224 and 369 days), SD: n = 3 BVZ: only SD and PD, shorter period of TTF
ORR: n = 5 (33.3%), VGPR: n = 2, PR: n = 3, MR: n = 1, SD: n = 6
Anti-DKK-1 antibody (3–40 mg/kg) Trend toward increase of bone + antimyeloma agents + zolendronic mineral density and bone strength acid (hip and spine) in anti-DKK-1 arm
STX 6 mg/kg iv., day 1 + 15/28 days + DEX 40 mg days 1–4, days 9–12, days 17–20/28 days (DEX was added to single agent STX if PD or 8 months in one patient (4%). The authors conclude that further studies are necessary to evaluate the beneficiary of lucatumumab in combination with other established antimyeloma agents, such as IMiDs and PIs [17] . Milatuzumab
CD74 is an essential chaperone of the MHC class II membrane protein family, which is preferentially involved in antigen presentation for immune response and initiating survival pathways and B-cell proliferation [44,45] . It exhibits high expression on malignant B cells and limited expression on normal tissue cells, qualifying CD74 as a potential therapeutic target in B-NHL lymphoma and MM [46] . In several clinical trials milatuzumab has already been successfully applied in patients with relapsed or refractory B-NHL, either as single agent or in combination with other drugs [47,48] . In vitro studies have already demonstrated that milatuzumab in combination with doxorubicin, BTZ or dexamethasone exhibits synergistic antimyeloma effects with increased apoptosis and growth inhibition rate [46] . In xenograft mouse models with disseminated MM, milatuzumab in combination with BTZ significantly prolonged survival rate [46] . In a Phase I dose-escalating trial, milatuzumab was applied as single agent in refractory and relapsing myeloma patients. In detail, 25 highly pretreated patients with only short response rates to prior treatment regimen received milatuzumab doses of 1.5, 4.0, 8.0 or 16.0 mg/kg administered twice
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10.2217/imt.15.118
Review Thanendrarajan, Davies, Morgan et al.
Targeted therapy Myeloma cells
Targets CS1 (SLAMF7) CD38 CD40 CD74 CD20
Monoclonal antibodies Elotuzumab Daratumumab Dacetuzumab Lucatumumab Milatuzumab Rituximab
Microenvironment
Targets IL-6 BAFF RANK-L DKK-1 KIR VEGF
Monoclonal antibodies Siltuximab Tabalumab Denosumab Anti-DKK-1 (BHQ880) Anti-KIR (IPH2101) Bevcizumab
Figure 2. Targeted therapy in multiple myeloma: overview of potential targets and monoclonal antibodies.
weekly for 4 weeks. Although no objective response was noted, at least 26% (n = 5) of the 19 patients who have completed the treatment expressed SD for at least 3 months, and even one patient remained in SD for 17 months. Taking the heavily pretreated and refractory patient population in consideration, milatuzumab seems to have the predicate to become a potent antimyeloma drug in combination with other agents (Table 3) [18] . Targeting the microenvironment Siltuximab
It is well-known that IL-6 weakens the antimyeloma efficacy of glucocorticoids, and promotes proliferation and drug resistance of MM cells [49,50] . In preclinical in vitro studies with human myeloma cell lines, Voorhees et al. have provided clear evidence that the antiIL-6 mAb siltuximab (CNTO 328) enhanced the cytotoxic activity of dexamethasone. This property was applicable for BTZ- and glucocorticoid-resistant human myeloma cell lines, and was preserved in the presence of human BMSCs. A clear, synergistic antimyeloma effect was noted in the combined application of dexamethasone and siltuximab, and addition of BTZ further improved the cytotoxic activity of this combination [49] . Moreover, Hunsucker and colleagues demonstrated that siltuximab synergistically accelerated the cytotoxicity of melphalan in human myeloma cell lines [50] . In a Phase I clinical trial with application of single agent siltuximab in patients with B-NHL, MM and Castleman disease, the authors came to conclusion that no dose-related or cumulative toxicities
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Immunotherapy (Epub ahead of print)
were standing out across all disease indications, and a dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease [19] . In a Phase II, multicenter clinical study siltuximab was utilized alone (n = 14) or in combination with dexamethasone (n = 39) in patients with RRMM with more than two prior treatments, including BTZbased regimen [20] . Siltuximab as single agent did not show any response, but in combination with dexamethasone it achieved a response rate of 23% (17%: PR, 6%: MR), including efficacy in dexamethasonerefractory disease. The median TTP was 4.4, PFS was 3.7 and OS was 20.4 months in the combination therapy arm, respectively. Overall, infectious problems were frequently noted, in terms of upper respiratory infections (14%), pneumonia, oral candidiasis and cellulitis (8% each). Hematological toxicities were also often noted, but manageable in total [20] . More and more clinical trials are conducted in which siltuximab is incorporated in earlier phases of the disease and in combination with IMiDs and PI, for example, in high-risk smoldering and newly diagnosed myeloma patients (Table 3) . Tabalumab
Survival of plasma cells in MM cells is mainly depending on interaction between malignant plasma cells and the bone marrow microenvironment. A very essential part of this microenvironment is the B-cell activating factor (BAFF), which belongs to the group of B-lymphocyte stimulators [51] . It is highly produced by osteoclasts and mesenchymal stroma cells and binds to
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NMM and ineligible for HD-chemo (Phase III)
DARA + BTZ + MEL + PRED vs BTZ + MEL + PRED
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NA
NCT02195479
NCT02316106
Ref.
NCT01998971
NCT02252172
BTZ: Bortezomib; CBR: Clinical benefit rate; CFZ: Carfilzomib; CR: Complete remission; C/W: Continue with; DARA: Daratumumab; DEN: Denosumab; DEX: Dexamethasone; DKK-1: Dickkopf-1; DZB: Dacetuzumab; EFS: Event-free survival; HD: High dose; iv.: Intravenous; LEN: Lenalidomide; MM: Multiple myeloma; MEL: Melphalan; NMM: Newly diagnosed MM; ORR: Overall response rate; PCB: Placebo; PD: Progressive disease; POM: Pomalidomide; PR: Partial remission; PRED: Prednisone; RRMM: Refractory and relapsing MM; SD: Stable disease; SMM: Smoldering multiple myeloma; STX: Siltuximab; TABA: Tabalumab; THAL: Thalidomide; TTP: Time to progression; VGPR: Very good partial remission.
+ BTZ + MEL + PRED + BTZ + THAL + DEX + POM + DEX + CFZ + DEX + CFZ + LEN + DEX
+ BTZ + DEX
NMM or RRMM (Phase I) DARA
+ DEX 40 mg iv. or PO, once a week for a maximum of 2 years or until disease progression or unacceptable toxicity, whichever comes first vs Same as above without DAR
DARA 16 mg/kg iv., 1 × weekly for 8 weeks, then 1 × every other week for 16 weeks, then 1 × every 4 weeks until PD, unacceptable toxicity or end of study (maximum up to 5 years) + LEN 25 mg PO days 1–21 of each 28-day cycle, for a maximum of 2 years or until disease progression or unacceptable toxicity, whichever comes first.
DAR + LEN + DEX vs LEN + DEX
+ PRED 60 mg/m2, PO, 1 × daily, on days 1–4 (cycle 1–9) vs Same as above without DARA
BTZ 1.3 mg/m2 SC, 2 × w, in weeks 1, 2, 4 and 5 (cycle 1), 1 × week in weeks 1, 2, 4 and 5 (cycles 2–9), + MEL 9 mg/m2 PO, 1 × daily,
DARA 16 mg/kg iv., 1 × weekly, for 6 weeks (cycle 1), every 3 weeks (cycle 2–9), every 4 weeks (until PD or unacceptable toxicity or study end)
vs 16 mg/kg IV, 1 × week (cycle 1), 1 cycle = 8 weeks
NMM and ineligible for HD-chemo (Phase III)
DARA monotherapy
DARA 16 mg/kg iv., 1 × weekly (cycle 1), every other week (cycle 2 + 3) every 4 weeks from cycle 4 to 7, every 8 weeks from cycle 8 to 20, 1 cycle = 8 weeks vs 16 mg/kg iv., 1 × week in cycle 1, very 8 weeks (cycle 2–20)
Daratumumab
Smoldering MM (Phase II)
Application
CD38
Indication monoclonal antibody/ combination
Target
Table 3. Application of monoclonal antibodies in treatment of multiple myeloma in ongoing Phase I, II and III clinical trial listed on www.clinicaltrials.gov.
Monoclonal antibody therapy in multiple myeloma
Review
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RRMM (Phase II)
CD38 (cont.)
Immunotherapy (Epub ahead of print)
RRMM (Phase Ib)
SAR + BTZ + CYC + DEX
SAR + POM + DEX
SAR (escalating dose) day 1, 8, 15, 22 (1st cycle), then day 1 and 15 + POM 4 mg days 1–21/28 days + DEX 40 mg day 1, 8, 15, 22 in 28 days cycle
SAR (escalating dose) days 1, 8, 15, 22 and 29 (1st cycle), then days 1 and 15 (subsequent cycles) + BTZ 1.3 mg/m2 SC days 1, 4, 8, 11, 22, 25, 29, 32 (1st cycle), then weekly days 1, 8, 15, 22 (cycle 2–12) + CYC 300 mg/m2 PO days 1, 8, 22, 29 (1st cycle), then days 1, 8, 15 (cycle 2–12) + DEX 20 mg PO/iv. days 1, 4, 8, 11, 15, 22, 25, 29, 32 (1st cycle), then if patients 75 years: DEX 20 mg days 1, 8, 15, 22 + maintenance (after cycle 12): SAR (at initial assigned dose) + DEX 20 mg once every 28 days
SAR (escalating dose) days 1, 8, 15, 22/28 days (1st cycle) days 1 and 15/28 days every other cycle
SAR 5 mg/kg or 10 mg/kg day 1 and 15/28 days + CFZ 20–27 mg/m2 (in standard application)
SAR (escalating dose) day 1 and 15 (every cycle) or day 1, 8, 15 and 22 (1st cycle) + day 1 and 15 every other cycle + LEN 25 mg PO days 1–21/28 days + DEX 40 mg PO day 1, 8, 15, 22/28 days
DAR 16 mg/kg iv., 1 w (cycle 1–3), 3 w (cycle 4–9), 4 w (>cycle 10) + BTZ 1.3 mg/m2 SC days 1, 4, 8 and 11 /21 days (8 cycles) + DEX 20 mg, days 1, 2, 4, 5, 8, 9, 11 and 12 (8 cycles) 1 cycle = 21 days vs same as above without DAR
DAR 16 mg/kg iv: 1 × w (cycles 1 + 2), 1 × 2 w (cycles 3 + 6); once only (on day 1) during treatment cycles seven onward. + LEN 25 mg PO days 1–21/28 days + DEX 40 mg 1 × w (20 mg, w, >75 years or BMI
