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Blood Reviews 30 (2016) 101110

Contents lists available at ScienceDirect

Blood Reviews
journal homepage: www.elsevier.com/locate/blre

REVIEW

Monoclonal antibodies A new era in the treatment of


multiple myeloma
Tomas Jelinek, Roman Hajek
a
b

Department of Hematooncology, University Hospital Ostrava, 17. listopadu 1790, 708 52 Ostrava, Czech Republic
Faculty of Medicine, University of Ostrava, Syllabova 19, 703 00 Ostrava, Czech Republic

a r t i c l e

i n f o

Keywords:
Monoclonal antibodies
Multiple myeloma
Bone disease
Daratumumab
Elotuzumab
Siltuximab
Lorvotuzumab
Pembrolizumab
Denosumab
BHQ880

a b s t r a c t
Monoclonal antibodies (mAbs) are currently the most investigated therapeutic compounds in oncology, but
there is no monoclonal antibody approved in the treatment of multiple myeloma (MM). Nevertheless several
really promising molecules are under investigation in phase III clinical trials. Dominantly daratumumab (antiCD38) and elotuzumab (anti-CS1) showed extraordinary effectiveness in phase I/II trials. The toxicity was
acceptable which is important for their addition to standard anti-myeloma agents like proteasome inhibitors
or immunomodulatory drugs. Monoclonal antibodies such as denosumab (anti-RANKL) or BHQ880 (anti-DKK-1)
are investigated also in the management of myeloma bone disease. This review is focused on the most promising
mAbs, their mechanisms of action and the rationale of use. Practically all available results have been described. If
the ongoing trials conrm the efcacy and safety of mAbs, they would become an important part of MM
treatment that would be translated in the further improvement of therapeutic outcomes.
2015 Elsevier Ltd. All rights reserved.

1. Introduction
Multiple myeloma ranks together with diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) amongst three
of the most common hematological malignancies. This plasma cell
disorder represents approximately 1% of all malignant tumors and
its incidence is estimated to be 6 cases per 100,000 persons per year
[1,2]. The introduction of autologous stem cell transplantation (ASCT)
as well as novel agents such as immunomodulatory drugs (thalidomide
and lenalidomide) and proteasome inhibitors (bortezomib), has
dramatically improved treatment outcomes of myeloma patients. At
present, median overall survival (OS) of patients eligible for ASCT is 6
8 years with one third of these patients living more than 10 years [3,
4]. In elderly patients ineligible for ASCT the median OS is 46 years
[5]. However, despite clear treatment advances, virtually all myeloma
patients will eventually relapse. Patients who relapse after bortezomib
and either thalidomide or lenalidomide, the so called double refractory patients, have a median OS of only 9 months [6]. This clearly demonstrates that there is a need for new treatment approaches that would be
able to overcome a dismal course of the disease in these patients. A
plethora of novel mechanisms and agents have been investigated
recently. New generations of proteasome inhibitors (carlzomib,
ixazomib, oprozomib) and third generation of immunomodulatory
Corresponding author at: Department of Hematooncology, University Hospital
Ostrava, 17. listopadu 1790, 708 52 OSTRAVA, Czech Republic.
E-mail addresses: tomas.jelinek@fno.cz (T. Jelinek), roman.hajek@fno.cz (R. Hajek).

http://dx.doi.org/10.1016/j.blre.2015.08.004
0268-960X/ 2015 Elsevier Ltd. All rights reserved.

drugs (pomalidomide) have been tested in many clinical trials, whereas


carlzomib and pomalidomide have already been approved for clinical
use in several countries. Agents with novel mechanisms of action such
as deacetylase inhibitors, mTOR/Akt inhibitors, kinesin spindle protein
inhibitors (Arry-520), monoclonal antibodies and many others have
been investigated in depth [7,8]. Monoclonal antibodies represent the
most promising group of agents with unique mechanism of action in
the treatment of multiple myeloma itself as well as in the treatment of
bone disease accompanying approximately 80% of myeloma patients,
being the most common complication in MM.
Bone disease and the skeletal complications associated with bone
pain, pathological fractures requiring surgery and/or radiation, hypercalcemia and spinal cord compression can be devastating and seriously
affect the quality of life and survival rate [9]. The main underlying cause
of bone disease in MM is the predominance of bone resorption over
bone production, respectively the superiority of osteoclasts over osteoblasts, resulting in the development of lytic lesions and/or osteoporosis
[10]. At present, bisphosphonates remain the cornerstone in the treatment of multiple myeloma bone disease, nevertheless the better understanding of the biology of bone disease has led to the development of
many novel agents. Several of them are monoclonal antibodies targeting
certain molecules such as RANKL, Dickkopf-1 or sclerostin that play a
crucial role in the pathogenesis of bone disease.
This review is focused on the current knowledge of monoclonal antibodies in the treatment of multiple myeloma and in the management
of myeloma bone disease. All available results of clinical trials investigating mAbs are summarized in Tables 1 and 2.

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T. Jelinek, R. Hajek / Blood Reviews 30 (2016) 101110

Table 1
Results of clinical trials conducted in RRMM patients.
Study
Monotherapy
Thalidomide
[77]
Bortezomib
[78]
Carlzomib
[79]
Lenalidomide
[80]
Pomalidomide
[81]
Two-drugs regimen
Len/Dex
[82]
Pom/Dex
[83]
Three-drugs regimen
Len/Dex/Btz
[84]
Len/Dex/Cfz
[85]
Len/Dex/Ben
[86]
Monoclonal antibodies
Daratumumab
[23]
Daratumumab
[26]
Dara/Len/Dex
[27]
Elotuzumab
[31]
Elo/Btz/Dex
[32]
Elo/Btz/Dex
[33]
Elo/Len/Dex
[34]
Elo/Len/Dex
[35]
Elo/Len/Dex
[37]
Siltuximab
[45]
Sil/Btz
[47]
Sil/Btz/Mel/Prednisone
[46]
Lorvotuzumab
[55]
Lor/Len/Dex
[56]

Phase

Median # of prior lines of therapy

ORR (%)

CR (%)

II

84

25

2.3

II

333

38

II

257

23.7

0.4

II

102

17

II

221

18

III

177

61

14.1

III

302

31

II

64

64

25

II

52

76.9

5.7

I/II

29

52

I/II

32

42

106

29

I/II

20

75

15

35

4.5

28

47

II

152

13

66

NA

29

82

Ib/II

101

84

14

III

646

79

NA

II

55

II

142

55

11

II

52

88

28

37

44

56

II

NA not applicable.

2. Monoclonal antibodies in the treatment of multiple myeloma


2.1. Daratumumab (HuMax-CD38)
Many anti-CD38 monoclonal antibodies have been investigated in
the past. Several of them such as SAR650984 (Sano), MOR03087
(Morphosys) or Ab79 (Takeda) are currently in the early phases of clinical testing, but daratumumab (Genmab/Janssen) seems to be the most
promising. Daratumumab is a human IgG1 monoclonal antibody
targeted against CD38, that is a 46 kDa transmembrane glycoprotein
[11]. This molecule is an ectoenzyme (cyclic ADP ribosylhydrolase)
regulating the intracytoplasmic concentration of calcium, but it also
behaves as a receptor, modulating interactions between cells and cooperating in transmembrane signal transmission [12]. Under normal
conditions, CD38 is expressed at relatively low levels on the cell

surface of myeloid and lymphoid cells as well as on some other tissues (neurons, epithelia, striated muscle) [13]. Myeloid cells are represented dominantly by neutrophils, eosinophils and basophils as
well as CD14++ CD16 monocytes [14], lymphoid cells by most natural killer (NK) cells, mature T lymphocytes, B lymphocytes and plasma
cells, respectively [15], (Fig. 1). Pluripotent hematopoietic precursor
cells (HPC) that are crucial for long-term marrow recovery do not
express CD38 at all. Overexpression of CD38 is seen in a majority of
lymphoid tumors, but on malignant plasma cells in multiple myeloma
this antigen is highly expressed (CD38 ++) in comparison to other
cell types [16] making it an attractive target for antibody therapy.
Daratumumab, as well as other monoclonal antibodies, possess a
broad spectrum of killing activities. ADCC (antibody-dependent cellmediated cytotoxicity) is the killing of an antibody-coated target
cell by a cytotoxic effector cell through a nonphagocytic process,

T. Jelinek, R. Hajek / Blood Reviews 30 (2016) 101110

103

Table 2
Results of clinical trials investigating mAbs in the management of bone disease.
Study/ref.
Denosumab
Body et al. [67]
Fizazi et al. [69]

Vij et al. [68]


Henry et al. [70]
Lipton et al. [71]

BHQ880
Iyer et al. [75]
Munshi et al. [87]

Drug/dose

Study type

Number of patients

Denosumab sc. 0.10.31.03.0 mg/kg vs


Pamidronate 90 mg i.v. monthly
Zoledronic acid 4 mg i.v. or
Pamidronate 90 mg i.v.
monthly vs
Denosumab sc.
180 mg monthly or 180 mg/12 weeks
Denosumab 120 mg sc.
monthly
Denosumab 120 mg sc. monthly vs
Zoledronic acid 4 mg i.v. monthly
Denosumab 120 mg sc. monthly vs
Zoledronic acid 4 mg i.v. monthly

Phase I, randomized, double-blind, multi-center study

54 patients
(25 MM, 29 BC)
111 patients
(50 PC, 47 BC, 15 MM, 6 other)

BHQ880 i.v. 3102040 mg/kg (MTD) monthly vs


Zoledronic acid 4 mg i.v. monthly
BHQ880 10 mg/kg i.v. monthly

Phase II randomized, open-label, multi-center study

Phase II single-arm study

96 patients (MM)

Phase III, randomized double-blind, active-controlled study

1786 patients
(702 NSCLC, 180 MM, 904 other)
5723 patients
(2046 BC, 1901 PC, 1776 other or MM)

Three identically designed, double-blind phase III trials

Phase IB, open-label, dose-determining study

28 patients (MM)

Single-arm, open-label, phase II study

25 patients (SMM)

MM multiple myeloma, BC breast cancer, PC prostate cancer, NSCLC non-small-cell lung cancer, SMM smoldering multiple myeloma.

characterized by the release of the content of cytotoxic granules or by


the expression of cell death-inducing molecules. Effector cells that
mediate ADCC include natural killer cells, monocytes, macrophages,
neutrophils, eosinophils and dendritic cells [17]. CDC (complementdependent cytotoxicity) is the next mechanism of action, when the
binding antibody initiates the complement system also known as complement cascade. The end result is a membrane attack complex that
literally makes a hole within the cell membrane, causing cell lysis and

death [18]. Other mechanisms of action are ADCP (antibody-dependent


cellular phagocytosis) by macrophages and direct induction of MM cell
apoptosis [19]. The mechanisms of action are clearly described in Fig. 2.
Finally, it is important to mention that the mechanism of action of
daratumumab (also elotuzumab) is strongly dependent on the function
of host immune system and effector cells (NK cells, T cells, macrophages). These monoclonal antibodies are likely to act synergistically
with treatment modalities that stimulate host anti-myeloma immunity,

Fig. 1. Expression of CD38 on bone marrow cells of patient with MM. Weak positivity for CD38 is detected on a part of leukocytes (green), monocytes (dark blue), on most of lymphocytes
(yellow) including immature forms of B-cells (purple) and a small proportion of mature B-cells (light blue). High expression is detected on plasma cells (red). Analyses made by the
ow cytometer FACSCantoII using acquisition software Diva 6.0 (Becton Dickinson) and analysis software Innicyt 1.6 (Cytognos). pos = CD38 positive cells, neg = CD38 negative
cells, = border of positivity/negativity.

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T. Jelinek, R. Hajek / Blood Reviews 30 (2016) 101110

with median of 5 prior treatment lines were reported at ASCO 2015 by


Lonial et al. ORR was 29.2% (31/106), with 3% of complete responses
(CR), 10% of very good partial responses (VGPRs), and 18% of partial responses with median time to progression 3.7 months. Infusion related
reactions (42.5%) were mainly grade 1/2 during the rst infusion
(grade 3 4.7%; no grade 4) [26].
At ASH 2014 (American Society of Hematology) the rst results
of a multicenter study phase I/II evaluating the combination of
daratumumab + lenalidomide + dexamethasone were presented.
Available preliminary efcacy data from 20 patients demonstrated
marked decrease in paraprotein in all patients; 15/20 patients achieved
PR or better (ORR = 75%), 6/20 with VGPRs and 3/20 with CR. The most
frequent (N 30% patients) adverse events (AEs) were neutropenia and
diarrhea, nevertheless this combination had a favorable safety prole
with manageable toxicities in RRMM [27].
2.2. Elotuzumab (HuLuc63)

Fig. 2. Mechanisms of action of daratumumab.

so the combination approaches may be more effective than monotherapy [20]. For example, combination with immunomodulatory drugs
(IMIDs) may improve clinical benet as these agents enhance Tand NK-cell-mediated immune responses. As proteasome inhibition
stimulates apoptosis, reduces angiogenesis, and can increase the
susceptibility of MM cells to NK cell-mediated killing, combination
with bortezomib or carlzomib may also be effective [2022].
Daratumumab was brought to the clinic in a phase I/II study, involving patients with relapsed/refractory multiple myeloma (RRMM) who
had received at least 2 prior lines of therapy [23,24]. Thirty-two heavily
pre-treated patients were enrolled in part 1 of the study, the median
number of prior lines of therapy was 6 and 75% of patients were double
refractory (to both lenalidomide and bortezomib). Amongst patients
treated at doses of 4 mg/kg and above, overall response rate (ORR) (partial response and better) was 42%, which is a remarkable result considering single agent efcacy. The most common adverse events reported
were infusion related reactions (IRRs) in 30% of patients during the
rst infusion. Since implementation of steroids before all infusions and
dilution of the trial drug, no serious IRRs were reported. In part 2, the
dose-expansion phase, 30 patients received 8 mg per kilogram of
daratumumab and 42 received 16 mg per kilogram, overall 72 patients
with a median of four prior treatments. The ORR was 36% in the cohort
that received 16 mg per kilogram with median PFS of 5.6 months. Infusion-related reactions were mild (71% of patients had an event of any
grade, and 1% had an event of grade 3) [25]. After a review of phase I/
II obtained data, the US FDA designated daratumumab a breakthrough
therapy, a designation that reects the agent's potential to improve patient outcomes. After this US FDA designation a larger phase II study
with daratumumab monotherapy in RRMM patients with 3 prior
lines of therapy was conducted. Preliminary results of 106 patients

Elotuzumab is a humanized IgG1 monoclonal antibody targeted


against the cell surface glycoprotein CS1 (also known as SLAMF7,
CRACC, CD2 subset-1 or CD319). This surface antigen is highly
expressed on MM cells and normal plasma cells, also at a lower level
on natural killer cells, NK-like T (NKT) cells, and a subset of CD8 positive
T cells. Little to no expression is detected on resting cells of the immune
system, hematopoietic stem cells and cells of other tissues [28,29]. The
function of CS1 on MM cells remains unclear. Elotuzumab exerts antimyeloma activity dominantly via NK-cell-mediated ADCC through
both direct activation and engagement of NK cells [30].
The rst-in-human study phase I evaluating elotuzumab as a single
agent in patients with RRMM did not show promising results. Thirtyve patients with a median of 4.5 prior lines of therapy were enrolled,
no objective responses were observed and 26% of patients were classied as having stable disease, the remaining had progression of disease
[31]. On the other side, subsequent studies of elotuzumab in combination with either lenalidomide and dexamethasone or bortezomib and
dexamethasone have demonstrated impressive results.
Jakubowiak et al. presented the results of a phase I study evaluating
the efcacy of elotuzumab in combination with bortezomib and dexamethasone in 28 enrolled patients with RRMM. Twenty seven patients
were evaluable (a median of prior MM therapies 2), PR or better
were achieved by 47% (13/27) of patients with 7% (2/27) of CRs. The
most frequent grade 3 to 4 adverse events were lymphopenia (25%)
and fatigue (14%) [32].
Preliminary data of phase II trial comparing the combination of
elotuzumab, bortezomib and dexamethasone vs bortezomib and dexamethasone alone in 152 patients with RRMM (13 previous therapies)
were presented at ASCO 2015 also by Jakubowiak et al. Median progression free survival (PFS) was 9.7 months in the elotuzumab arm vs 6.9
months (HR 0.71, P = 0.08), ORR was 66% vs 63%. This study met the
primary endpoint, PFS was longer in the elotuzumab arm than in the
comparative arm (HR 0.71), with only limited added toxicity [33].
Lonial et al. published a phase I study evaluating elotuzumab,
lenalidomide, and dexamethasone in patients with RRMM. Twentynine patients with a median of 3 prior MM therapies were enrolled,
ORR was 82% (23/28) of treated patients, with VGPR in 29% (8/28)
and CR in 4% (1/28) of patients. The most frequent grade 3 to 4 toxicities
were neutropenia (36%) and thrombocytopenia (21%) [34].
Recently at ASH 2014, the nal results for the phase Ib/II study of
elotuzumab in combination with lenalidomide and dexamethasone in
patients with RRMM were presented.
In phases I and II together, 101 patients had been treated with more
than 1 prior MM therapy. Overall, ORR was 84%, a stringent complete response/complete response (sCR/CR) was seen in 14% of patients, 43%
had VGPR. Median PFS was 29 months. Serious AEs were experienced
by 58% of patients, most commonly pneumonia (12%), 10% of patients
had infusion related reactions. In this study, elotuzumab in combination

T. Jelinek, R. Hajek / Blood Reviews 30 (2016) 101110

with len/dex demonstrated robust and clinically meaningful efcacy as


measured by ORR and also PFS [35].
At ASCO 2015 an interim analysis of phase III, randomized study of
len/dex with or without elotuzumab was reported. Overall 646 patients
with median of 2 previous therapies were randomized to receive either
elo/len/dex or len/dex, median PFS was 19.4 vs 14.9 months, 2-year PFS
was 41% vs 27%, ORR was 79% vs 66% (P = 0.0002). Grade 34 adverse
events 15% were neutropenia (25%) and anemia (15%), infusion related reactions occurred in 10% of patients with elotuzumab (mostly
grades 12). A clinically relevant 30% reduction in risk of progression
or death was seen in elo/len/dex arm vs len/dex arm [36,37].

2.3. Siltuximab (CNTO 328)


By the end of the 20th century a plethora of monoclonal antibodies
targeted against Interleukin-6 (IL-6) had been investigated [38]. The
most promising of them seemed to be siltuximab, a chimeric monoclonal antibody with a high afnity and specicity for human IL-6 [39]. IL-6
is a pleiotropic cytokine that has been shown to play a critical role in the
pathogenesis of multiple myeloma and other B-cell lymphoid malignancies [4042]. This cytokine is known to enhance the proliferation and
the survival of myeloma cells and also to contribute to the resistance
to bortezomib, melphalan and dominantly to corticosteroid-induced
apoptosis [43,44]. Thus, the blockade of IL-6 by a monoclonal antibody
could logically improve the outcomes of multiple myeloma patients.
The efcacy and safety of siltuximab as a single agent and in combination with dexamethasone were evaluated in a phase II multicenter
study in patients with RRMM. A total of 53 patients were enrolled
with a median number of 4 prior lines of MM therapy. There were no responses to single-agent siltuximab, with 8 (8/13) patients achieving stable disease and 5 (5/13) with disease progression. In the siltuximab +
dexamethasone arm there were 38 patients, only 11% (4/38) achieved
PR, the rest had stable disease or disease progression. Hematological
toxicity (thrombocytopenia, anemia and neutropenia) was responsible
for the majority of adverse events of grade 3 or 4 [45].
San Miguel et al. recently published the results of phase II randomized study of bortezomib + melphalan + prednisone (VMP) with or
without siltuximab in patients with newly diagnosed multiple myeloma
(NDMM) ineligible for ASCT. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP plus siltuximab. The overall
response rate was 88% in S + VMP and 80% in VMP, and at least very
good partial response rates were 71% and 51% (P = 0.0382), respectively. With a CR rate of 27% in siltuximab plus VMP and 22% in VMP, the
study did not conrm its hypothesis that the addition of siltuximab
would increase the CR rate by at least 10%. Grade 3 adverse event incidences were 92% in S + VMP and 81% in VMP (P = 0.09), with trends
toward more hematological events and infections on S + VMP. In conclusion, the addition of siltuximab to VMP did not improve the CR rate
or long-term outcomes [46].
The most recent phase II randomized clinical trial of siltuximab +
bortezomib vs bortezomib alone in patients with RRMM was published
by Orlowski et al. A total of 281 patients with at least one prior line of
anti-myeloma therapy were randomized. The overall response rate for
the siltuximab + bortezomib arm and bortezomib only arm was 55%
vs 47% (P = 0.213), complete response rate was 11% vs 7%, median
PFS was 8.0 and 7.6 months (P = 0.345) and median OS was 30.8 vs
36.8 months (P = 0.103). Most common adverse events grade 3 or
higher were neutropenia and thrombocytopenia, together with all
grade infections occurring more frequently in siltuximab + bortezomib
arm. The addition of siltuximab to bortezomib did not appear to improve PFS or OS in this group of patients [47].
To complete this chapter, in April 2014, the FDA granted full approval to siltuximab for the treatment of patients with multicentric
Castleman disease (MCD) who are human immunodeciency virus
(HIV) negative and human herpesvirus-8 (HHV-8) negative [48].

105

2.4. Lorvotuzumab mertansine (IMGN901, BB-10901)


Like brentuximab vedotin in the treatment of Hodgkin lymphoma
and other CD30 + lymphoid malignancies, lorvotuzumab mertansine
(LM) too is an antibody-drug-conjugate. In this case, the monoclonal
antibody is targeted against CD56 and is conjugated to the cytotoxic
maytansine. Once bound to CD56 on the surface of the target cell the
conjugate is internalized, maytansine is released, which in turn inhibits
tubulin polymerization and results in cell death. Maytansine is a natural
product, originally derived from the Ethiopian shrub Maytenus serrata,
that is approximately 2001,000 fold more cytotoxic than the Vinca
alkaloids [49,50].
CD56 is a membrane glycoprotein, also known as neural cell adhesion molecule (N-CAM), that is expressed on neural tissues and essentially on all human NK cells and a subset of cytotoxic T cells [51,52]. In
pathological conditions, CD56 is expressed in various malignant tissues
including small cell lung cancer, neuroblastoma, ovarian cancer and
others [53]. Interestingly, CD56 is not present in normal plasma cells,
thus the normal phenotype of plasmocytes is CD19 + CD56. On the
other hand, CD56 is strongly expressed in up to 78% of MM cases [54].
There is only a limited number of clinical data compared to other
monoclonal antibodies. As a single agent LM was initially evaluated in
phase I study in 37 RRMM patients with a median number of 6 prior
lines of anti-myeloma therapy. Fifteen of 37 patients (41%) showed
some clinical benet (stable disease for at least 3 months), including
only 5% (2/37) partial responses [55]. Lorvotuzumab mertansine was
also tested in combination with lenalidomide and dexamethasone in
clinical trial phase I. Forty-four patients with a median number of 2
prior lines of MM therapy were enrolled. The ORR was 56% (22/39),
with 28% (11/39) VGPRs and 2% (1/39) of CRs. The most common adverse events were peripheral neuropathy, diarrhea, neutropenia and
thrombocytopenia [56]. Lorvotuzumab mertansine proved its clinical
benet, but due to its neurotoxicity and less robust responses than expected, its further development in the treatment of multiple myeloma
won't be pursued (personal communication with Professor Berdeja).
2.5. Other monoclonal antibodies under development
Currently many other monoclonal antibodies targeting various antigens on the surface of myeloma cells or other molecules involved in
their proliferation are under investigation, several of them have reached
phase I/II of clinical trials and have showed some clinical efcacy
warranting further testing.
2.5.1. IPH2101 and IPH2102 (lirilumab, BMS-986015)
NK cells elicit cytotoxicity against multiple myeloma. However, malignant plasma cells express HLA class I molecules as ligands to NK cell
killer-cell immunoglobulin-like receptors (KIRs) as an NK cell immune
evasive strategy. IPH2101 is a human IgG4 monoclonal antibody against
inhibitory KIR on the surface of NK cells that blocks the inhibitory KIRligand relationship to recover or augment NK-cell function against myeloma cells [57,58].
Benson et al. published a phase I clinical trial with IPH2101 as a single agent in 32 patients with RRMM. This study showed that anti-KIR
antibody is safe and tolerable but no objective responses were seen
and stable disease was achieved by 34% of patients [58]. Same authors
have recently reported the results of a phase I study in 15 RRMM patients treated with combination of IPH2101 and lenalidomide with no
corticosteroids. Objective responses were observed in 33.3% of patients
and median PFS was 24 months [59].
Lirilumab (IPH2102) is a second generation anti-KIR mAb that was
evaluated in a phase I trial in patients with solid tumors and hematological malignancies. There are several trials planned in combination with
check point inhibitors or cytotoxic antibodies in myeloma patients as
well [60].

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2.5.2. Pembrolizumab (MK-3475), pidilizumab (CT-011), nivolumab


(BMS-936558)
All these monoclonal antibodies rank amongst immune checkpoint
inhibitors that target the programmed cell death receptor (PD-1)
expressed on the surface of activated T cells. If one of PD-1 ligands
(PD-L1 and PD-L2) binds to PD-1, T cells become inactive one of the
natural mechanisms of how the body regulates the immune system.
Many tumor cells overproduce PD-L1, allowing malignant cells to inhibit T cells from attacking the tumor [61]. Monoclonal antibodies that
block this inhibitory interaction of PD-1 on T cells with its ligand PDL1 from malignant cells have achieved remarkable results dominantly
in solid tumors but also in hematological malignancies [62].
There are multiple checkpoint inhibitor clinical trials ongoing or
planned in multiple myeloma. Phase I/II studies with pembrolizumab
plus pomalidomide and dexamethasone or plus lenalidomide and dexamethasone in RRMM patients and phase II trial with pembrolizumab
plus lenalidomide post ASCT are ongoing. Pidilizumab is investigated
in combination with lenalidomide in phase I/II clinical trial in RRMM patients. Finally nivolumab alone or in combination with ipilimumab
(CTLA-4 blocking antibody) or lirilumab (2nd generation anti-KIR antibody) is being evaluated in a phase I clinical trial in relapsed/refractory
lymphoma and myeloma patients [62].
2.5.3. Indatuximab ravtansine (BT062)
Indatuximab ravtansine is an antibody-drug conjugate, comprising
the anti-CD138 chimerized mAb 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. CD138 (Syndecan-1)
is highly overexpressed on various solid tumors and in hematological
malignancies, and represents one of the most specic target antigens
for identication of malignant plasma cells. The results of a phase I/II
trial that evaluated the combination of BT062 with lenalidomide and
dexamethasone were presented at ASH 2014. Preliminary data from
45 RRMM patients with median of 3 prior anti-myeloma therapies indicate that BT062 is well tolerated in combination with len/dex, overall
response rate was 78% [63].
Many other mAbs such as lucatumumab and dacetuzumab (antiCD40), ulocuplumab (anti-CXCR4) or MFGR1877S (anti-FGFR3) are
currently being investigated.
3. Monoclonal antibodies in the management of myeloma bone
disease
3.1. Denosumab
Denosumab is a fully human monoclonal antibody targeted against
RANKL with high afnity and specicity [64]. The disruption of the
RANKL/RANK/OPG pathway causes the imbalance of bone resorption
and bone production in MM induced bone disease. The binding of
RANKL to its receptor RANK leads to the maturing process and increased
activity of osteoclasts, dominantly through the metabolic pathway of
NF-B. Osteoprotegerin (OPG) binds to RANKL preventing it from binding to RANK, which in turn inhibits osteoclast differentiation and activation [65,66]. Malignant plasma cells increase the expression of RANKL
and reduce the expression of OPG leading to the development of
osteolytic lesions. All these qualities make RANKL a desirable target for
monoclonal antibody therapy.
Several phase I and II studies including dominantly patients with
metastatic solid tumors and multiple myeloma compared denosumab
with bisphosphonates (BPs) and showed at least a similar efcacy of
denosumab in comparison to BPs [67,68]. In phase II trial Fizazi et al.
investigated the effect of denosumab in patients with bone metastases
despite on-going treatment with intravenous bisphosphonates. This
study proved that denosumab prevents skeletal related events (SREs)
and inhibits bone resorption even in patients who are refractory to BP
therapy [69]. The rst phase III trial including myeloma patients was

published by Henry et al. Eligible patients were randomly assigned to


receive monthly subcutaneous denosumab 120 mg (n = 886) or
intravenous zoledronic acid 4 mg (dose adjusted for renal impairment;
n = 890). Denosumab was non-inferior to zoledronate in delaying the
time to rst on-study SRE (P = 0.0007) [70].
A meta-analysis of major phase III, identically designed, randomized,
double-blind trials of patients with metastatic solid tumors or multiple
myeloma was published by Lipton et al. In total 5723 patients were
randomized to receive either 120 mg subcutaneous denosumab or
4 mg intravenous zoledronic acid. Overall, denosumab was superior to
zoledronic acid in delaying time to rst on-study SRE by a median of
8.2 months, reducing the risk of a rst SRE by 17% (P b 0.001). Disease
progression and overall survival were similar between treatments. Hypocalcemia was more common for denosumab while osteonecrosis of
the jaw occurred at a similar rate (P = 0.13) [71]. At the ASCO meeting
in 2013, a subset analysis of 180 MM patients included in this large
meta-analysis was presented. The denosumab arm was comparable
with zoledronic acid arm with respect to the occurrence of SREs, but
inferior overall survival (1 year OS of 83%) occurred in patients receiving
denosumab in comparison to patients receiving zoledronate (1 year OS of
97%). Nevertheless, OS results in the MM cohort are difcult to interpret
due to the small numbers of MM patients and imbalances in baseline
disease characteristics [72]. A larger phase III trial (NCT00330759)
focusing on myeloma patients is currently ongoing.
The toxicity of denosumab appears to be low, mainly asthenia and
hypocalcemia. Osteonecrosis of the jaw appeared in 2% of patients in
meta-analysis and was comparable to zoledronate. Caution is needed
regarding the fact that anti-RANKL strategy affects the immune system
and may possibly lead to an increase in infection rates especially in MM
patients who are immunocompromised [9].
3.2. BHQ880 (anti-DKK-1)
Dickkopf-1 (DKK-1), a soluble inhibitor of the Wnt signaling pathway, plays a crucial role in osteoblast dysfunction observed in multiple
myeloma. This glycoprotein is secreted by myeloma cells and inhibits
osteoblast activity. Its serum level correlates with focal bone lesions in
MM, it is increased in symptomatic MM at diagnosis but also in relapse,
whereas its level is normal in asymptomatic MM or in the plateau phase
of the disease [9,73].
BHQ880 is the rst-in-class, fully human IgG1 anti-DKK-1 monoclonal antibody. The rst proof of its potential activity was published by
Fulciniti et al., who showed that BHQ880 increases the osteoblast differentiation and inhibits malignant plasma cell growth and development
of osteolytic lesions [74]. Recently, a phase IB multicentre study of
BHQ880 in combination with anti-myeloma therapy and zoledronic
acid in 28 patients with RRMM was published. There was a general
trend toward increased bone mineral density observed over time, nevertheless the relative effect of BHQ880 cannot be fully established due
to concomitant zoledronic acid and anti-myeloma therapy administration. Administration of BHQ880 was well tolerated and the results
presented herein suggest that further research into the effects of
BHQ880 in MM is warranted [75].
Romosuzumab (AMG785) is another investigational humanized
monoclonal antibody, that inhibits the activity of sclerostin, and that
has been successfully tested in phase II study in postmenopausal
women [76]. Clinical trials in MM are about to start soon [9].
4. Conclusion
Monoclonal antibodies represent new and interesting group of
agents with a unique mechanism of action distinct from currently
used drugs in the treatment of multiple myeloma. The toxicity seems
to be minimal which is important for the incorporation of mAbs
into combination with other more toxic drugs. Daratumumab and
elotuzumab are the most promising molecules for several reasons.

T. Jelinek, R. Hajek / Blood Reviews 30 (2016) 101110

Target antigens (CD38, CS1) are highly expressed on the surface of most
malignant plasma cells, while they are not present on other tissues or
hematopoietic stem cells, so the expected side effects are not serious.
The most common adverse events were infusion related reactions,
which were easily manageable with adequate premedication in form
of glucocorticoids, antihistamines and acetaminophen. The efcacy of
these two antibodies is exceptional with ORR about 80% in combination
with lenalidomide and dexamethasone in patients with relapsed

107

refractory disease. Daratumumab in monotherapy reached ORR of 36%


in patients with median 4 prior anti-myeloma therapies, which is considered to be an unprecedented treatment outcome in such pretreated group of patients. These successful results have led to the initiation of many phase III clinical trials (Table 3). The rst preliminary results of phase III trial comparing elo/len/dex vs len/dex in 646 patients
were presented at ASCO and EHA 2015 and conrmed the benet in
the terms of ORR and PFS with clinically relevant 30% reduction in risk

Table 3
Phase III clinical trials investigating mAbs in the treatment of MM.
Title

Phase 3 study comparing daratumumab, lenalidomide,


and dexamethasone (DRd) vs lenalidomide and
dexamethasone (Rd) in subjects with relapsed or
refractory multiple myeloma

A phase 3 study comparing daratumumab, lenalidomide


and dexamethasone (DRd) vs lenalidomide and
dexamethasone (Rd) in subjects with previously
untreated multiple myeloma who are ineligible for
high dose therapy

Regimens
Experimental arm

Active comparator

Daratumumab i.v. 16 mg/kg, days 1, 8, 15, 22 (2


cycles), days 1, 15 (4 cycles), day 1 (onwards);
Lenalidomide orally 25 mg/day, days 1-21;
Dexamethasone orally 40 mg/week;
28 days long cycle, until progression or
unacceptable toxicity

Lenalidomide
orally 25 mg/day,
days 121;
Dexamethasone
orally 40

Daratumumab i.v. 16 mg/kg, days 1, 8, 15, 22


(2 cycles), days 1, 15 (4 cycles), day 1
(onwards);
Lenalidomide orally 25 mg/day, days 121;
Dexamethasone orally 40 mg/week;
28 days long cycle, until progression or
unacceptable toxicity

Phase 3 study comparing daratumumab, bortezomib


and dexamethasone (DVd) vs bortezomib and
dexamethasone (Vd) in subjects with relapsed or
refractory multiple myeloma

Daratumumab i.v. 16 mg/kg, days 1, 8, 15, 22


(3 cycles), every 4 weeks (onwards)
Bortezomib i.v. 1.3 mg/m2, days 1, 4, 8, 11
(8 cycles);
Dexamethasone orally 20 mg/day,
days 1, 2, 4, 5, 8, 9, 11, 12 (8 cycles);
21 days long cycle, until progression or
unacceptable toxicity

A phase 3, randomized, controlled, open-label study of


VELCADE (bortezomib) melphalanprednisone
(VMP) compared to daratumumab in combination
with VMP (D-VMP), in subjects with previously
untreated multiple myeloma who are ineligible for
high-dose therapy

Daratumumab i.v. 16 mg/kg, once weekly


(1 cycle), every 21 days (8 cycles), every 4

Phase 3, randomized, open label trial of


lenalidomide/dexamethasone with or without
elotuzumab in relapsed or refractory multiple
myeloma (MM)

A phase 3, randomized, open label trial of


lenalidomide/dexamethasone with or without
elotuzumab in subjects with previously untreated
multiple myeloma

weeks (onwards)
Bortezomib i.v. 1.3 mg/m2,
days 1, 4, 8, 11, 22, 25, 29, 32 (9 cycles);
Melphalan orally 9 mg/m2/day, days 14
(9 cycles);
Prednisone orally 60 mg/m2/day, days 14
(9 cycles);
42 days long cycle, until progression or
unacceptable toxicity

mg/week;
28 days long cycle,
until progression
or unacceptable
toxicity
Lenalidomide
orally 25 mg/day,
days 121;
Dexamethasone
orally 40
mg/week;
28 days long cycle,
until progression
or unacceptable
toxicity
Bortezomib i.v. 1.3
mg/m2, days 1, 4,
8, 11;
Dexamethasone
orally 20 mg/day,
days 1, 2, 4, 5, 8, 9,
11, 12;
21 days long cycle
(8 cycles)
Bortezomib i.v. 1.3
mg/m2,
days 1, 4, 8, 11, 22,
25, 29, 32
Melphalan orally 9

mg/m2/day, days
14;
Prednisone orally
60 mg/m2/day,
days 14;
42 days long cycle
(9 cycles)
Elotuzumab i.v. 10 mg/kg, days 1, 8, 15, 22
Lenalidomide
(2 cycles), days 1, 15 (onwards)
orally 25 mg/day,
Lenalidomide orally 25 mg/day, days 121;
days 121;
Dexamethasone orally 28 mg on elotuzumab
Dexamethasone
dosing days, otherwise orally 40 mg/week and orally 40 mg,
i.v. 8 mg/weekly;
days 1, 8, 15, 22;
28 days long cycle, until progression or
28 days long cycle,
unacceptable toxicity
until progression
or unacceptable
toxicity
Dexamethasone
Elotuzumab i.v. 10 mg/kg, days 1, 8, 15, 22
(2 cycles), days 1, 15 (16 cycles), 20 mg/kg, day 40 mg/day orally,
days 1, 8, 15, 22;
1 (onwards)
Lenalidomide 25
Dexamethasone orally 28 mg on elotuzumab
dosing days otherwise orally 40 mg/week and
mg/day, days
i.v. 8 mg/weekly (schedule stays after 18 cycles 121;
unchanged);
28 days long cycle,
Lenalidomide 25 mg/day, days 121;
until progression
28 days long cycle, until progression or
or unacceptable
unacceptable toxicity
toxicity

Condition

Estimated NHI identier


enrollment

Relapsed or
refractory
multiple
myeloma

560
patients

NCT02076009

Newly
diagnosed
multiple
myeloma,
ineligible for
HDM

730
patients

NCT02252172

Relapsed or
refractory
multiple
myeloma

480
patients

NCT02136134

Newly
diagnosed
multiple
myeloma,
ineligible for
HDM

700
patients

NCT02195479

Relapsed or
refractory
multiple
myeloma

646
patients

NCT01239797

Newly
diagnosed
multiple
myeloma,
ineligible for
HDM

750
patients

NCT01891643

108

T. Jelinek, R. Hajek / Blood Reviews 30 (2016) 101110

of progression or death in elotuzumab arm. Siltuximab repeatedly in


several randomized trials failed to show clinical efciency and this
drug does not present a benet for multiple myeloma patients.
Denosumab (anti-RANKL) antibody is actually an approved drug for
metastatic solid tumors, but not for myeloma bone disease. The results
of ongoing clinical trials designed for myeloma patients are highly expected. BHQ880 or romosuzumab are the products of the better understanding of the pathophysiology of bone disease, but they are yet far
from approval in the treatment of MM. In conclusion, daratumumab
and elotuzumab could become a standard part of anti-myeloma therapy
very soon and could signify a substantial progress in the management of
this malignant disorder.
Practice points
Elotuzumab or daratumumab in combination with lenalidomide and
dexamethasone reach ORR about 80% in relapsed/refractory myeloma
patients that represents substantial progress in the management of
this group of patients.
Monoclonal antibodies are safe, the most common adverse events are
infusion related reactions which are easily manageable with adequate
premedication.
Siltuximab and lorvotuzumab mertansine do not represent a benet
for multiple myeloma patients.
Denosumab and BHQ880 have a potential to become a part of supportive care in the management of myeloma bone disease.

Research agenda
Evaluate the efcacy of mAbs in induction therapy before ASCT in
NDMM.
Evaluate the efcacy of mAbs in four combinations with PIs, IMIDs and
corticosteroids in NDMM and RRMM and dene the most benecial
combination.
Combine daratumumab or elotuzumab with other monoclonal antibodies that augment antitumor immune responses e.g. immune
check point inhibitors (anti-PD1 antibodies) or anti-KIR antibodies.
Investigate the exact mechanism of action, dominantly the synergistic
effect with other drugs that stimulate host immune system
(PIs, IMIDs, check point inhibitors).

Conict of interest statement


The authors report no relevant conicts of interest.
Acknowledgments
This work was supported by the Moravian-Silesian Region grants
MSK 02680/2014/RRC and MSK 02692/2014/RRC; grants by MH CZDRO-FNOs/2015 and 15-29667A, by The Ministry of Education, Youth
and Sports (Institutional Development Plan of University of Ostrava in
2015); projects SGS01/LF/20142015, SGS02/LF/20142015, SGS03/
LF/20152016 and by grant IGA of The Ministry of Health 15-29667A.
The authors want to give special thanks to Mgr. Eva Jarosova for the administrative support. The authors would like to thank Mgr. Pavla
Vsianska for the ow cytometric gures and Ing. Petra Novotna for the
help with graphic processing of gures.
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