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Blood Reviews
journal homepage: www.elsevier.com/locate/blre
REVIEW
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.
102
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
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.
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,
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]
BHQ880
Iyer et al. [75]
Munshi et al. [87]
Drug/dose
Study type
Number of patients
54 patients
(25 MM, 29 BC)
111 patients
(50 PC, 47 BC, 15 MM, 6 other)
96 patients (MM)
1786 patients
(702 NSCLC, 180 MM, 904 other)
5723 patients
(2046 BC, 1901 PC, 1776 other or MM)
28 patients (MM)
25 patients (SMM)
MM multiple myeloma, BC breast cancer, PC prostate cancer, NSCLC non-small-cell lung cancer, SMM smoldering multiple myeloma.
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.
104
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
105
106
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
Table 3
Phase III clinical trials investigating mAbs in the treatment of MM.
Title
Regimens
Experimental arm
Active comparator
Lenalidomide
orally 25 mg/day,
days 121;
Dexamethasone
orally 40
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
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
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).
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