Daratumumab, Elotuzumab, and the

Development of Therapeutic Monoclonal

Antibodies in Multiple Myeloma
JP Laubach1, CE Paba Prada1, PG Richardson1 and DL Longo1

There has been substantial progress in clinical outcomes for patients with multiple myeloma (MM). This encouraging trend
derives in large part from the increasing number of effective therapeutic options and the ability because of this to achieve
higher quality responses to treatment. The approval of both daratumumab and of elotuzumab in combination with
lenalidomide and dexamethasone, in late 2015, was a notable achievement in the field, as daratumumab and elotuzumab
represent the first monoclonal antibodies available for use in MM. Given their unique mechanisms of action and favorable
side effect profiles, daratumumab and elotuzumab have considerable potential as therapeutic partners with agents in
other drug classes and in different clinical settings ranging from newly diagnosed to relapsed disease. This review
discusses the development of daratumumab and elotuzumab as well as other monoclonal antibodies currently being
evaluated for use in MM.

Multiple myeloma (MM) is a hematologic malignancy character-
ized by the presence of clonal plasma cells within the bone
marrow and clinical manifestations of lytic bone lesions, hyper-
calcemia, renal impairment, and anemia.1,2 MM is the second
most common hematologic malignancy and it is estimated that
in 2016 30,330 individuals in the United States were diagnosed
with the disorder.3
Long-term patient outcomes have continued to improve over
the past three decades because of advances in MM manage-
ment.4,5 Nonetheless, relapsed MM in particular remains an
important area of unmet medical need as nearly all patients with
MM ultimately relapse and require subsequent lines of therapy
before eventually dying of the disease.
Reecting the rapid progress of MM drug development in
recent years, six regimens received approval from the US Food
and Drug Administration (FDA) in 2015. Among these were
daratumumab monotherapy and elotuzumab in combination
with lenalidomide and dexamethasone, which represent the rst
regimens incorporating monoclonal antibodies (mAbs) approved
in MM.
There has been strong scientic and clinical impetus behind
the development of mAbs in MM, as advances in the laboratory
have broadened the understanding of MM biology and led
to identication of an array of therapeutic targets. Moreover,
the use of mAbs, such as rituximab, in other hematologic
1
Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Correspondence: JP Laubach (JacobP_Laubach@DFCI.harvard.edu)
Received 7 October 2016; accepted 31 October 2016; advance online publication 2 November 2016. doi:10.1002/cpt.550
malignancies610 as well as the impact of mAbs in solid malignan-
cies11,12 has been associated with improvement in clinical out-
comes and favorable toxicity proles.
This review includes discussion of the current management
algorithm for MM, the mechanisms of action of daratumumab
and elotuzumab, the clinical trial development of these agents
that led to the FDA approval, as well as the manner in which
these two drugs are optimally used within the overall MM treat-
ment landscape. There is also discussion of new, emerging mAbs
currently being evaluated in MM in clinical trials.
The current approach to multiple myeloma management
Patients with newly diagnosed MM are typically treated with two
or three-drug induction regimens incorporating an immunomo-
dulary drug (IMID) and/or proteasome inhibitor in combination
with a glucocorticoid and, in some instances, an alkylating agent.
Clinical trial data suggest that better long-term outcomes can be
achieved with three rather than two-drug combinations, so, when
feasible, this approach is preferred.13,14
Patients eligible for high-dose therapy and autologous stem cell
transplantation (ASCT) generally receive three to six cycles of
induction therapy before undergoing stem cell mobilization.
These patients then have the option to proceed immediately with
ASCT vs. store cells and defer ASCT to a later point in their
management. There are data to suggest that either one or two

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rounds of high-dose melphalan and ASCT following induction
therapy with lenalidomide and dexamethasone confers benet
with respect to progression-free and overall survival.15,16 There
are preliminary data from the ongoing IFM/DFCI 2009 trial as
well as the EMN02/HO95 MM trial to suggest that early trans-
plant is associated with a signicant improvement in progression-
free survival but no difference in overall survival.17,18 Patients
who opt against early transplant receive additional cycles of
induction therapy with the aim of attaining a deep response to
therapy.
Accumulating evidence suggests that, in the aftermath of
induction therapy with or without transplant, long-term mainte-
nance treatment with lenalidomide until progression enhances
long-term outcome.1922 There is also evidence that in high-risk
patients dened by cytogenetic ndings, such as deletion of 17p
or 1p, translocation t(4;14) or t(14;16), post-ASCT consolida-
tion and maintenance with lenalidomide, bortezomib, and dexa-
methasone is feasible without excessive toxicity.23
At the time of disease progression, various factors are consid-
ered in decisions regarding the next line of therapy.24 Combina-
tions using the IMIDs, proteasome inhibitors, alkylating agents,
and glucocorticoids have long been mainstays of treatment for
relapsed and refractory MM. Liposomal doxorubicin in combina-
tion with bortezomib has also been an option in this setting25
and panobinostat (a histone deacetylase inhibitor) plus bortezo-
mib and dexamethasone can now be considered as well following
the FDA approval in 2015.26 The FDA label for carlzomib was
expanded in 2015 to include carlzomib plus lenalidomide and
dexamethasone based on results of the ASPIRE trial,27 whereas
the combination of ixazomib (an orally bioavailable proteasome
inhibitor), lenalidomide, and dexamethasone represents the rst
all-oral IMID plus proteasome inhibitor combination.28
The approvals of daratumumab and elotuzumab in combina-
tion with lenalidomide and dexamethasone have further expand-
ed options for relapsed and refractory MM.
Mechanism of action of daratumumab and elotuzumab in
multiple myeloma
Daratumumab is a humanized immunoglobulin G1K anti-CD38
mAb that exerts antitumor activity through antibody-dependent
cell-mediated cytotoxicity and complement-dependent cytotoxic-
ity29 as well as antibody-dependent cellular phagocytosis (see
Figure 1).30 More recently, it has been shown that, in addition
to these mechanisms, daratumumab decreases a subpopulation of
regulatory T cells that express CD38 and in concert increases help-
er and cytotoxic T-cell populations, suggesting that the agent pos-
sesses an additional immunotherapeutic effect on tumor cells.31
Elotuzumab is a humanized immunoglobulin G1K mAb that
targets signaling lymphocytic activation molecule family member
7 (SLAMF7), a cell surface glycoprotein that is expressed at a
high level on both normal and tumor plasma cells, and at a lower
level on other lymphocyte subsets, including natural killer,
CD81 T cells, and dendritic cells.32 Elotuzumabs antitumor
effects derive from its ability to inhibit binding of MM cells
to bone marrow stromal cells and induce antibody-dependent
cell-mediated cytotoxicity (Figure 2).33 In addition, elotuzumab
82
induces cytoxicity against SLAMF7-expressing MM cells through
activation of SLAMF7-expressing natural killer cells.34 Of note,
natural killer cell activation in this context has been shown to be
dependent on the signaling molecule EAT-2, which is present in
natural killer cells but not found in MM cells.
CLINICAL DEVELOPMENT OF DARATUMUMAB AND
ELOTUZUMAB
Daratumumab
Clinical development of daratumumab began with a phase I
dose-escalation and dose-expansion study.35 Thirty-two patients
in the dose escalation portion had received a median of 5.5 lines
of prior therapy, and 75% were refractory to lenalidomide and
bortezomib. Daratumumab was administered weekly for 8 weeks
at doses ranging from 0.00524 mg/kg. Dose-limiting toxicities
included an episode of grade 3 anemia at 0.1 mg/kg and an epi-
sode of grade 3 Aspartate Transaminase increase at 1 mg/kg. A
maximum tolerated dose (MTD) was not reached. In the dose
expansion portion of the study, 72 patients with a median of
four prior lines of therapy received either 8 mg/kg or 16 mg/kg.
The overall response rate (ORR) was higher (36% vs. 10%) and
the median progression-free survival was longer (5.6 vs. 2.4
months) in patients treated at 16 mg/kg than at 8 mg/kg. High-
grade toxicities were infrequent and included neutropenia,
thrombocytopenia, anemia, pneumonia, and hyperglycemia. Infu-
sion reactions were common, occurring in 71% of patients in the
dose expansion group, most of which were grade 1 or 2. In terms
of pharmacokinetic characteristics, elimination of daratumumab
was rapid at doses of 2 mg/kg or lower and decreased at higher
doses. In the dose expansion phase at the 16 mg/kg dose, the
mean half-life of daratumumab was 9.0 days after the rst dose
and 10.6 days after subsequent doses.
In the phase II SIRIUS trial, 106 patients with a median of
ve prior lines of therapy, all of whom were refractory to both a
proteasome inhibitor and an IMID, received daratumumab
16 mg/kg once weekly for 8 weeks, every other week for 16 weeks,
and every 4 weeks thereafter.36 The response rate among this
group was 29%, with 34% of patients experiencing clinical benet
(minimal response or better). The median progression-free sur-
vival was 3.7 months and 12-month overall survival was 64.8%.
The most common grade 3/4 toxicities were anemia, thrombocy-
topenia, and neutropenia, which occurred in 24%, 19%, and 12%
of patients, respectively. No other grade 3/4 toxicities occurred in
more than 3% of patients. Infusion reactions were noted in 42%
of patients, 5% of which were grade 3 and the remainder grade
1 or 2.
On the basis of data from the phase I and II clinical trials dem-
onstrating the safety and efcacy of daratumumab, the agent
received accelerated approval from the FDA in November 2015
for patients who have received at least three prior lines of therapy,
including a proteasome inhibitor and IMID, or who are refracto-
ry to both a proteasome inhibitor and an IMID.
Regimens incorporating daratumumab in combination with
standard agents, such as lenalidomide and bortezomib, have also
yielded promising results. In a phase I/II study evaluating daratu-
mumab plus lenalidomide and dexamethasone in relapsed and/or
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Figure 1 Daratumumab induces death of the myeloma cell through multiple mechanisms, including complement dependent cytotoxicity (CDC), antibody-
dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), apoptosis stimulated by antibody cross-linking, and modu-
lation of enzymatic activity. cADPR, cyclic ADP ribose; MAC, membrane attack complex; NAD, nicotinamide adenine dinucleotide.

refractory MM, for example, no dose-limiting toxicities were not-
ed at doses of daratumumab ranging from 216 mg/kg and the
16 mg/kg dose was selected for further study in combination
with standard lenalidomide and dexamethasone.37 In the second
phase of the study, 32 patients with a median of two prior lines
of therapy had an ORR of 81%, including a stringent complete
response of 25%, complete response rate of 9%, and a very good
partial response rate of 28%.
This study was followed by the phase III POLLUX study eval-
uating lenalidomide and dexamethasone with or without daratu-
mumab in patients with MM who received a least one prior line
of therapy.38 In this study, 569 patients who had received one or
more prior lines of therapy received lenalidomide plus dexameth-
asone with or without daratumumab. The incorporation of
daratumumab was associated with improvement in response rate
(93% vs. 76%; P < 0.0001) and rate of complete response or

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Figure 2 Elotuzumab induces death of the myeloma cell through inhibi-
tion tumor cell binding to bone marrow stromal cells, antibody dependent
cell-mediated cytotoxicity, and activation of natural killer cells expressing
signaling lymphocytic activation molecule family member 7 (SLAMF7).
better (43% vs. 19%; P < 0.0001). The rate of minimal residual
disease negativity (1 tumor cell per 105 white cells) was signicant-
ly higher among patients treated with daratumumab (22.4% vs.
4.6%; P < 0.001). The progression-free survival rate at 12 months
was superior in the daratumumab arm (83.2% vs. 60.1%) and there
was a 63% reduction in risk of disease progression or death.
Daratumumab has also proven to be an effective therapeutic
partner with bortezomib, as evidenced by results from the phase
III CASTOR trial.39 In this study, 498 patients who had received
at least one prior line of therapy received bortezomib plus dexa-
methasone with or without daratumumab. The incorporation of
daratumumab was associated with improvement in 12-month
progression-free survival (60.7% vs. 26.9% with median not
reached vs. 7.2 months; hazard ratio 5 0.39); response rate
(82.9% vs. 63.2%; P < 0.001), rate of very good partial response
or better (59.2% vs. 29.1%; P < 0.001), and rate of complete
response or better (19.2% vs. 9.0%; P 5 0.001). Grade 3/4 events
were uncommon overall and similar across the two treatment
groups except for hypertension, which occurred in 6.6% of those
in the daratumumab group vs. 0.8 in the control group. All-grade
diarrhea, upper respiratory infection, cough, dyspnea, and periph-
eral edema were more common in the daratumumab group.
Elotuzumab
Clinical development of elotuzumab began with a phase I dose-
escalation study involving 35 patients with relapsed and refractory
MM with a median of 4.5 lines of prior therapy who received elo-
tuzumab at doses ranging from 0.5 to 20 mg/kg every other
week.40 Elotuzumab was well tolerated overall and the MTD was
not reached up to the maximum planned dose of 20 mg/kg. There
were no responses to elotuzumab as a single agent; 26.5% of
patients experienced stable disease. With respect to pharmacoki-
netic characteristics, mean clearance decreased with higher doses
of elotuzumab, consistent with saturation of target-mediated
84
clearance. Moreover, saturation of SLAMF7 increased with higher
doses of elotuzumab, reaching a maximum level of saturation at
the 10 mg/kg dose. The degree of target saturation observed at
the 10 and 20 mg/kg doses was equivalent. The mean half-life of
elotuzumab at the 10 mg/kg dose was 4.6 days.
Despite the lack of response to elotuzumab monotherapy
observed in the phase I study, it was anticipated based on the
agents mechanism of action it could serve as an effective thera-
peutic partner with standard therapies in MM and further studies
were undertaken. This hypothesis was rst evaluated in two phase
I trials in relapsed and/or refractory MM, one of elotuzumab
plus lenalidomide and dexamethasone,41 and the other of elotu-
zumab plus bortezomib and dexamethasone.42 No dose-limiting
toxicities were noted in either trial up to the maximum planned
elotuzumab dose of 20 mg/kg and the MTD was not reached.
The response rate with elotuzumab plus lenalidomide and
dexamethasone was 82% among patients with median of 3 prior
lines of therapy, and 48% with elotuzumab plus bortezomib and
dexamethasone among patients with 2 prior lines of therapy.
A subsequent randomized phase II trial evaluating 10 and
20 mg/kg doses of elotuzumab in combination with lenalidomide
and dexamethasone showed a promising response rate of 84%
and median progression-free survival of 32.5 months (10 mg/kg)
and 25 months (20 mg/kg).43 This was followed by a random-
ized, phase III ELOQUENT 2 trial of lenalidomide and dexa-
methasone with or without elotuzumab in relapsed and
refractory MM.44 The incorporation of elotuzumab was associat-
ed with improvement in response rate (79% vs. 66%; P < 0.001)
as well as median progression-free survival (19.4 months vs 14.9
months; hazard ratio 5 0.70; P < 0.001). Of note, fewer com-
plete responses were observed in patients treated with elotuzu-
mab, which may have been due to interference by the therapeutic
mAb with results of electrophoresis. The rate of adverse events
was similar in the two groups, although fatigue, pyrexia, diarrhea,
constipation, and cough were more common in the elotuzumab
group. There was a higher rate of serious adverse events in the
elotuzumab group. Infusion reactions occurred in 10% of
patients treated with elotuzumab, most of which were grades 1/2.
Extended, 3-year follow-up of ELOQUENT 2 demonstrated
that the clinical benet associated with the addition of elotuzu-
mab to lenalidomide plus dexamethasone was durable, with a
27% reduction in the risk of disease progression or death (hazard
ratio 5 0.73; P 5 0.0014). There was also a strong trend toward
benet in overall survival associated with the three-drug regimen
(hazard ratio 5 0.77; P 5 0.0257).45
Based on results from the phase III study, the FDA approved
elotuzumab plus lenalidomide and dexamethasone for patients
with relapsed and refractory MM who have received one to three
prior lines of therapy.
Specific clinical scenarios of importance
There are a number of clinical scenarios that are of specic
importance to the optimal use of daratumumab and elotuzumab
in practice.
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Infusion reactions
As with other therapeutic mAbs, daratumumab and elotuzumab
are associated with infusion reactions, which manifest in various
ways, including headache, hypertension, hypotension, rhinitis,
wheezing, cough, dyspnea, nausea, vomiting, and rash. They are
estimated to occur in up to 50% of patients receiving daratumu-
mab and 10% of those who receive elotuzumab. Infusion reac-
tions typically occur with the rst or second dose of the drug and
are most often grade 1/2 in severity but higher-grade reactions
can occur. Thus, it is important to adhere to the recommended
schedule of premedications to lessen the frequency and severity
of these reactions.
In the case of daratumumab, premedications should include a
glucocorticoid, such as methylprednisolone, antihistamine, such
as diphenhydramine, and Tylenol. Our group also routinely
administers montelukast before daratumumab during the initial
cycles of treatment due to the relatively high rate of respiratory
symptoms encountered during or following the infusion, particu-
larly among patients with a history of asthma or chronic obstruc-
tive pulmonary disease. During the initial cycles of treatment, an
oral glucocorticoid is also recommended for 2 days following dar-
atumumab infusion as well to mitigate the risk of delayed infu-
sion reaction affecting respiratory function.
In the case of elotuzumab, oral dexamethasone 28 mg is
administered within 24 hours of the infusion and a dose of intra-
venous dexamethasone 8 mg is given immediately before treat-
ment. In addition, patients receive H1 and H2 blocking
antihistamines as well as Tylenol as premedications.
Laboratory assay interference
As humanized immunoglobulin GK mAbs, both daratumumab
and elotuzumab are detected on standard serum protein electro-
phoresis and immunoxation, and, thus, can affect interpretation
of this assay. This phenomenon of interference has potential
implications with respect to accurate classication of disease sta-
tus according to the International Myeloma Working Group cri-
teria.46 Thus, it is important to notify the laboratory performing
the serum protein electrophoresis procedures that a particular
patient is receiving mAb therapy.
A daratumumab-specic immunoxation electrophoresis reex
assay has been developed to allow for differentiation between dar-
atumumab and M-protein, which may be available for commer-
cial use in the future.47 There is no such interference assay for
elotuzumab at present.
It is important to note that in contrast to the effects on serum
protein electrophoresis/immunoxation, daratumumab does not
interfere with results of the serum-free light chain assay.48
Blood typing interference by daratumumab
CD38 is expressed on human red blood cells.49 Daratumumab
interferes with blood typing by binding to CD38 on the surface
of reagent blood cells and leads to a positive indirect Coombs
test.50 Treatment of reagent red cells with dithiothreitol, which
denatures cell surface CD38, represents one method to potential-
ly circumvent this issue. Blood blanks should be notied about
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 1 | JANUARY 2017
patients receiving daratumumab, and patients should undergo
typing and screening before the rst dose of daratumumab.
Renal dysfunction
Renal dysfunction is observed in approximately 2040% of
patients with newly diagnosed MM and a signicantly higher per-
centage of patients experience decreased renal function through-
out the course of the disease.51 The etiology is typically
multifactorial and related to paraprotein-mediated kidney injury,
hypercalcemia, dehydration, and drug effect. The ability to safely
administer chemotherapeutic agents in the setting of renal
impairment is therefore a priority in the management of MM.
Importantly, therapy-related renal toxicity has not been
observed in phase III trials evaluating elotuzumab44 or
daratumumab.39
In a phase Ib study evaluating elotuzumab plus lenalidomide
and dexamethasone in 26 patients with relapsed MM with a
range of renal function ranging from normal to severe to end-
stage, there were no signicant differences in mean and maxi-
mum elotuzumab serum concentrations or area under the curve
as a function of renal impairment.52 The rate of high-grade
toxicities was equivalent among patients with normal vs. impaired
renal function, and the response rate was similar across
the groups. These ndings indicate elotuzumab can be utilized in
this patient population with appropriate monitoring for
toxicities.
Other monoclonal antibodies currently in development
As shown in Table 1, numerous novel mAbs are currently in
development in MM.
Additional anti-CD38 monoclonal antibodies. In addition to daratu-
mumab, two other CD38-targeting mAbs are currently being
developed, including SAR650984 and MOR202. SAR650984
demonstrated signicant single agent activity in a phase I trial
involving 35 patients with relapsed and/or refractory MM who
had received a median of 6 prior lines of therapy.53 The MTD
was not reached, and the agent resulted in a response rate of
24%, including 6% complete and 18% partial responses. At doses
of >10 mg/kg, the rates of overall, complete, and partial response
were 33%, 11%, and 22%, respectively. Grades 3/4 pneumonia
occurred in three patients.
In a phase Ib study involving heavily pretreated patients with
relapsed and/or refractory MM, SAR650984 at doses of 10 or
20 mg/kg in combination with standard dose/schedule lenalido-
mide, the MTD once again was not reached and the combination
yielded a response rate of 50%.54 Twenty-ve percent of patients
treated at 10 mg/kg and 20% of those treated at 20 mg/kg
achieved a very good partial response, whereas 25% of patients
treated at 10 mg/kg and 30% of those treated at 20 mg/kg
achieved partial response.
There is an ongoing study of SAR650984 in combination with
pomalidomide and dexamethasone as well (NCT02283775).
MOR202 has been evaluated as monotherapy and in combi-
nation with pomalidomide or lenalidomide in an ongoing
phase I/IIa study (NCT01421186).55 Preliminary data indicate
85
Table 1 Antibodies being evaluated in myeloma
Antibody Target Phase
Isatuximab (SAR650984) Anti-CD38 III
MOR202 Anti-CD38 I/IIa
Milatuzumab Anti-CD74 I/II
Indatuximab ravtansine (drug conjugate) Anti-CD138 I/II
Tabalumab Anti-BAFF (B-cell activating factor) II
Siltuximab Anti-IL6 II
Lucatumumab Anti-CD40 I
Dacetumumab Anti-CD40 I
BHQ880 Anti-DKK1 II
Sotatercept (RAP-011) Activin receptor ligand trap IIa
huN901-DM1 (drug conjugate) Anti-CD56 I
Pembrolizumab Anti-PD1 II/III
Nivolumab Anti-PD1 II/III
Atezolizumab Anti-CD274 (PD-L1) I
IL6, interleukin 6; PD1, programmed cell death 1; PD-L1, programmed cell death ligand 1.

that MOR202 monotherapy and in combination with either
pomalidomide or lenalidomide is safe and generally well tolerat-
ed. An MTD has not been reached in the study to date. The
infusion duration for MOR202 at 2 h is relatively brief in com-
parison to daratumumab and the rate of infusion reactions is
low. Responses were observed in 33% of patients.
Siltuximab. Interleukin-6 is an attractive therapeutic target for
MM as it is known to be involved in the pathogenesis of
MM.56,57 The anti-interleukin-6 mAb siltuximab was evaluated
in a randomized phase II study of bortezomib plus melphalan
and prednisone with or without the antibody.58 The addition
of siltuximab led to a trend toward improvement in overall
response (88% vs. 80%) and a signicant improvement in
the rate of very good partial response or better (71% vs. 51%;
P 5 0.0382). However, there was no difference in progression-
free survival across the two arms of the study. Rates of high-
grade adverse events were similar overall, although patients
treated with siltuximab had a higher incidence of neutropenia
and thrombocytopenia.
Siltuximab was partnered with lenalidiomide, bortezomib,
and dexamethasone in a phase I trial in patients with newly
diagnosed MM.59 The MTD was reached at the rst dose level
of siltuximab at 8.3 mg/kg after one patient experienced grade
3 pneumonia and another patient had grade 4 thrombocytope-
nia. The most common high-grade adverse events were hema-
tologic, including neutropenia, thrombocytopenia, and
lymphopenia. The ORR was 91%, whereas the rates of com-
plete response and very good partial response were 9% and
45%, respectively.
A study of siltuximab in high-risk smoldering MM is ongoing
(NCT01484275).
Indatuximab ravtansine. Indatuximab ravtansine is an mAb con-
jugated to the maytansinoid DM4 toxin that targets syndecan 1
(CD138) expressed on plasma cells, and in preclinical studies
exerted antimyeloma activity by inhibiting tublin polymerization
and inducing cell cycle arrest.60 The compound has minimal
activity as a single agent61 yet there is interest in assessing its
potential in combination therapy. In an ongoing phase I/II study
in relapsed and/or refractory MM, the agent is being adminis-
tered in combination with lenalidomide and dexamethasone and
in a preliminary analysis produced an ORR of 78%.62 There were
two dose-limiting toxicities at a dose of 120 mg/m2 mucosal
inammation and anemia.
Monoclonal antibodies targeting programmed cell death
1/programmed cell death ligand 1
There is considerable interest in therapeutic strategies targeting
the programmed death 1 (PD-1) receptor and its ligand pro-
grammed cell death ligand 1 in MM. In vitro studies have shown
that blockade of PD-1/programmed cell death ligand 1 inhibits
growth of tumor cells, providing strong rationale for this
approach and numerous clinical trials evaluating this hypothesis
are underway.63,64 Examples of this include a phase I trial evaluat-
ing the combination of lenalidomide and dexamethasone plus the
anti-PD-1 mAb pembrolizumab in relapsed MM, in which the
combination led to an ORR of 76%, including 23% who
achieved a very good partial response.65 Of note, 41% of patients
were IMID-refractory and 18% were refractory to both IMID
and proteasome inhibitor.
Furthermore, in an ongoing phase II study, 24 patients with
relapsed MM, 75% of whom were refractory to both IMID and
proteasome inhibitor, received the anti-PD-1 mAb pembrolizu-
mab in combination with pomalidomide and dexamethasone.66

86 VOLUME 101 NUMBER 1 | JANUARY 2017 | www.wileyonlinelibrary/cpt

The ORR was 50%. The most common high-grade toxicities
were hematologic, including neutropenia, lymphopenia, and
thrombocytopenia. Several patients experienced autoimmune-
related toxicities, such as hypothyroidism, transaminitis, and
pneumonitis.
CONCLUSION
The approvals of daratumumab and elotuzumab in combination
with lenalidomide and dexamethasone in relapsed MM in late
2015 represented a major advance in MM therapeutics. The
availability of these novel regimens further increases the number
of treatment options available for relapsed disease. Moreover, the
unique antitumor mechanisms as well as the favorable toxicity
prole of both agents make them ideal partners in multi-agent
chemotherapy regimens that have the potential to produce deeper
and more durable responses for patients with both newly diag-
nosed and relapsed disease. Ongoing and future studies of these
agents will dene which combinations are most effective at differ-
ent stages of the disease, as well as the potential role for daratu-
mumab and elotuzumab in the context of maintenance therapy.
Other mAbs, particularly those targeting the immune check-
points PD-1 and programmed cell death ligand 1 are likewise
associated with considerable promise and results of ongoing stud-
ies evaluating these agents are awaited with interest.
ACKNOWLEDGMENTS
The authors thank Megan Hiserodt and Michelle Maglio for their editorial
assistance with the manuscript.
CONFLICT OF INTEREST
The authors declared no conflict of interest.
C 2016 American Society for Clinical Pharmacology and Therapeutics
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